Probably will be your first and second runs of some game. For me, it's Escape Plan. First run was 1:42:33, second was 1:09:24, for a hefty li'l timesave of 33:09. Interestingly, that's roughly the same margin between PB #2 and my current PB (36:39), but it took much longer to save that next 33 minutes!
I do run a much, much longer game (Infamous) but my biggest jump there is only about half as big (from 4:21:38 to 4:06:50). The difference between PB1 and 2 was practically nothing given how long the run is (4:40:37 -> 4:35:05). You'd think that the longer the run, more of a chance of it, but not in this case.
Let's see... so far my 2 biggest improvements have been Chip's Challenge Level Pack 1, from an 8:38:28 blind run to 4:35:14 second run, after having heavily worked on its ILs. That's a 4:03:14 improvement, longer than many runs get.
My biggest improvement though has been with FF9 "insanity%", on my third run- 39:10:01 first, 35:53:28 second, and 29:25:56 third. 6:27:32 is the second improvement there- with the first one being 3:16:33.
I've also had a couple other nice 'second run' improvements- CC1 dropped from 6:21:54 to a 5:04:52 (1:17:02 improvement), and CC2 has the potential to drop almost 10 hours from my winning blind race time of 13:26:08. Haven't practiced that at all yet, but once I have the puzzle solutions down I expect a time somewhere in the 3-5 hour range. What a difference knowing the solutions to 200 levels going in makes!
Jersey Devil. I went from 3:05:16 al the way down to 2:35:54. That's nearly a 30 minute improvement.
tetris worlds, from 52:15 in 2014, to 34:25 in 2016, a ~42% decrease. primarily due to improvements in other tetris games over time
PLatDB: For me it was, when I found out, how to skip the cutscenes in the game, which made an improvement of about half an hour.
Definitely Gears of War 2 All Collectibles Any% because it was the first run and it was terrible, but it was 4:20:10 and I lowered it to 3:15:58. Most of the previous run was watching where videos where the collectibles were.
Lufia 4 between my 2nd and 3rd run. Wouldve been more if I finished my 1st run, but had to give up that run as it was going well over 16 hours. The improvement was from a 13:38:30 to a 10:52:22. Close to 3 hour improvement. Cut another 2 hours since then (now at a 8:54)
I only did two single segment runs of Live A Live (most of the runners do ILs). My first run was 10 hours and then I found a ton of different strats doing ILs and did a 2nd run that came in at 6:07:xx.
So I guess that's about a 4 hour save.
Finding a strat that cut out half of a mission in Wing Commander 1, improving the IL time from a 3:40 to under 2 minutes.
In Monstrum my first run was 11m52s, and the second one was 6m47s. In a matter of game this is galactic improvement - 43%! For now my record is (for this video, of course) 4m23s (64% improvement)