A tie between Hunter and Hunted (C) and Requiem (BM). In both missions 47 is cornered from all directions and if this wasn’t a game, he was beyond fucked even if he’d put up a fight.
Hunter and Hunted
Once the mission starts you have approximately 10 seconds to flee your room or you’re ambused from every direction. Since 47 is a silent assassin, canonically speaking, he wouldn’t just shoot up the hotel. Let’s say he takes action way earlier or manages to escape the room in those 10 seconds, it would still be hard to get out of the hotel. Everyone is looking for the assassin that dresses up in other peoples clothes, so it would be highly suspicious if suddenly one SWAT guy abandons the squad and casually walks out of the building. On top of that, the only way to kill the commander is in direct line of sight for the pedestrians, who will obviously scream for help. Chances this mission would succeed irl are very low.
Requiem
Do I even have to explain? My guy lies dead in the coffin surrounded by countless armed goons. Even if 47 manages to kill a bunch of them, he would eventually die of bullet wounds. Saying professional difficulty is the most realistic, 9 out of 10 times you can only succeed this mission by doing 3 headshots when you’re dying. That doesn’t happen in real life. 47’s only chance would be to take the priest hostage, but even then they’ll start shooting eventually.
I also chose the H2SA end sequence because of Agent 17. He has the advantage and recognizes 47 from miles away. He’s also hard to find inside the building because he moves around when he hears 47 walk. That, and the high number of Russian mobsters swarmed throughout the city makes this a tricky one.