As in, the players not being acolytes and struggle to survive in the WH 40k universe? I know Dark Heresy makes PCs rather weak at the beginning, but it would still work, everything depends on the GM style.

Basically yes. It'd require something a bit different from the players themselves and a somewhat little more relaxed approach to skills, I would guess, but I see no particular reason why 40k itself doesn't work as 'just another Sci Fi universe'.

The specifics of it are:
- Most 'fantastic' elements are attributable to the Warp (meaning randomness and 'not good for your health/soul')
- There's a heavy near-absolutely real religious aspect

Otherwise, it's pretty straight. I knocked up a half 1930s Call of Cthulchu New York City setting on the planet Lind, wherein it'd be for 'in between' campaign games, allowing a familiar setting where there's not a single, overarching 'campaign thread', but it's more of a sprawling sand-box campaign where the player characters just exist and trudge on with their slightly-more interesting-than-others' lives.

So, in answer, yes, I think it'd work. You might want to draw more closely on some of the expanded rules though to give a bit more of a dynamic for things outside normal DH scope (running businesses via RT Profit Factors and so forth).

Yeah. My friends and i are planning to do a Necromunda inspired campaign with no inquisitorial involvement whatsoever. This means limiting some of the available classes and adding more from the radical's handbook, removing certain Acolyte/inquisition related skills/ciphers/secret language, etc.

The inquisition aspect of DH has never sat well with us. Far too limiting being tied down to always tied to some zealot, hunting demons, and cultists and xenos. So now we intend to swap an inquisitor with a crime boss/Gang Leader and do some exciting crime and/or gang warfare.

DH has basically replaced SLA Industries as my go to sci-fi/horror game now,

while SLA had a fun setting the rules were not even close to ballanced, and the combat rules needed a good amount of work, too many homerules were getting made and then i tried doing d20 modern and all that jazz,

heck ive been tempted to retool Mort, prolly put it in the Koronus expanse, so it isnt directly under imperial control, make Mr Slayer a halo device user, though i doubt my players would find it as funny as i would so i doubt ill do it

Yes, just like most systems, you could take the rules and make your own world with it.

Also, the fluff of the world in Warhammer 40k says that the empire of man is so spread so much, that many of the worlds are even unknown and lost by now, meaning that there might be humans that live in their own little part of the galaxy, not knowing much of what goes on elsewhere.

You could have Star Trek fighting Star wars with Battlestar Galactica and Babylon 5 in between in this universe if you want, then the imperium might find them and crush them all for being heretics

I was thinking of actually running a fantasy campaign with the dark heresy rules. Just remove all the hightech stuff and use primitive equipment that fitted my fantasy world. We ended up playing it in pathfinder though, as we always have been into the whole D&D RP, and run more normal DH stuff beside my campaign

Thank you for the replies so far, I've been thinking of starting my campaign with the PCs on board a passenger space ship, travelling to Scintilla, an unknown space force attacks the ship one day and the ship itself crashes in one part of Scintilla, the PCs get recovered and healed in a laboratory, and then their adventure begins. I think I am gonna base the story arround the ship attack.

How does it sound? How would you develop this story?

A good start. It lets the characters be very unfamiliar with the place they are in.

I'd suggest the first thing to do is to have the people that took care of them demand a compensation. TANSTAAFL as one of my fav Sci-Fi writers would have put it :-) Explain that the alternative is of course that they can donate their bodies to the construction of servitors. Then it is of course up to the characters if they want to play along and run an errand or two, or if they want to say "sure" and just walk away as soon as they are out of the lab. Both could give them some interesting opportunities.

One difficult thing could be the attacking of a spaceship close to Scintilla. Since that planet is a major tradehub it is pretty well guarded by the calixis fleet. Also, crahslanding a several kilometer long spaceship that is not at all capable of atmospheric flight tends to leave zero survivors. Maybe have a malfunction (or was it... sabotage?) of their landing shuttle causing it to crashland.

I'd suggest the players make up a group from the beginning so that they have a reason to stick together. They should be friends or at least aquaintances since before, preferrably with a common purpose. Also, make sure that this particular thing that they were traveling to Scintilla to do is no longer available for them. Maybe it took plenty of time before they recovered from the crash, so the entire cargo of fresh expensive fruit that they had invested their fortune (plus substantial loans) in has now gone rotten. Good thing is, they are reported as dead so as long as they stay below radar no loansharks will come looking for them.

Or if you want to plant the main plot of their adventures, then their very valuable cargo of suitcase size is not with them, and upon inspection turns out to have been stolen/salvaged from the wreckage. Now they need to get it back and maybe even get revenge! Was the sabotage even fixed to get to them? And are these seemingly friendly lab assistans maybe working for the same organisation?

This got me thinking. I planned it to be an attack at the start, but this got me thinking. I actually wrote in my campaign book that the PCs see some shady figures entering before they fall unconscious. It could be the start of an attack of an enemy, Chaos, Orks, Dark Eldar, who knows? I will sit and write me some.

It may be better to use Rogue Trader, but yeah, it could be done.