Without question, the MSX game I spent the most time with BY FAR is Pumpkin Adventure 3. That game is insanely long, but is IMHO the best RPG on the system, hands down, and I absolutely loved it. I guess I kind of had to, in order to spend probably somewhere around 100 hours on it. 
Other MSX games that I've spent a significant amount of time with are also RPGs, since RPGs do tend to be the longest-lasting games. That list includes games like Rune Worth, Emerald Dragon, and War of the Dead, though it's only the first of those three that I actually played to completion (Emerald Dragon frustrated me after a time and I wound up dropping it, and War of the Dead is a game I keep coming back to and am VERY CLOSE to finishing, but still haven't quite completed).
Beyond that, there are some longer games that I completed over the course of a week or two, but probably put a good 10+ hours into apiece -- games like Golvellius (both MSX1 and MSX2 versions), Metal Gear 2, Higemaru Makaijima, Maze of Galious, and probably a bunch of others I'm forgetting.
I've also spent way more time playing A Life M36 Planet: MotherBrain has been aliving than most, but that's because of the fan-translation project -- I played that game to completion at least four times over, and know it like the back of my hand at this point.
And on a similar note, I've spent way more time playing Izumic Ballade than most due to... well, actually completing it, for one, which is something I doubt many others have done given its buggy nature, its high difficulty level, and the Japanese language barrier. Plus, I've also partially fan-translated it, so I've spent a LOT of time digging into it and testing sections of it over and over -- though the fate of that project is still looking a bit grim, on account of the technical difficulties I've had with it. 
And finally, the two games I randomly keep coming back to -- the ones that I'll just pop in if I'm bored but don't know what I want to play -- are Protector and Kyokugen. Not sure why, but if I'm in the mood for some mindless fun, I'll turn to Protector, and if I'm in the mood to shoot stuff, I'll turn to Kyokugen. So I've probably put a sizable number of hours into both of those, too, at this point.
-Tom
Hmm, good question... I know I've sunk in a lot of time in games bij UMAX and ANMA at least. Pumpkin Adventure 3, NOSH, Troxx and Witch's Revenge come to mind especially.
Nemesis II and III have also seen some playtime, but apart from that, I think most of the time went into playing Tetris clones, puzzle-, and card-, and breakout-games like Solitaire Royale, Not Again, Troika, Gorby's Pipeline and Triplex, often while taking turns or playing against my mother. 
Oh, and Fruity Frank. Really should play some more of that game again.
Malaya's Treasure also consumed a lot of my time, even though I couldn't understand the story at the time.
I think the one game for me is MOG. Played it till my fingers bled, over and over. Man, I loved that game. I clearly remember when I first discovered (by my self) the CROSS item. I made screenshots with game-master and sent my discovery to MSX magazine. I told my self I was the first and only who found out about that hidden screen Yeah, it was long ago... but man, I played it.
