By Play do you mean DM or PC? Both play the game, just from different vantage points.
The hardiest to DM is Forgotten Realms. There is just too much there and too high level NPCs. Then when you start to take that stuff away, it somehow loses the fealing of FR.
The Hardest to PC in in Plancsape. So many factions and things going on. Hard to keep track of it all. That doesn't mean it isn't fun, though.
Ravenloft for me as a player was TOUGH. I lost five characters there, three to undead, two to unnamed THINGS, (and I MEAN Thing!!!) and one became a DarkLord...who was assasinated by my last Ravenloft PC.
I suppose I'll have to follow suit... Hardest to play as a PC is easily Dark Sun -- it's too brutal, even given all the extra crap you get for it.
The hardest to DM is easily Forgotten Realms, because of the sheer lack of "artistic license" the DM has (lest he alienate his players who have read and grokked every FR book, novel, or fan-composed poem).
Hardest to play is Dark Sun, agreed.
Hardest to DM would be, by far, Ravenloft. I have a very good memory when it comes to gaming material, so the Realms aren't a problem, but creating a horror atmosphere is more difficult.