No Spyderco folder fits my hand as well as the Police 3 and 4. That's my primary reason for carrying them. The Manix XL also has wonderful ergonomics, aside from the thumb ramp that's too far back for my hand.
When it comes to fixed blades, the Aqua Salt and Street Bowie are the most comfortable.
Two things prevent a lot of models from being comfortable for me.
1. Fingers grooves spaced for smaller hands (Delica) despite the handle being long enough for a comfortable hold.
2. The biggie, thumb ramps. Most thumb ramps are placed far too close to where the index finger is intended to go for the knife to be comfortable for me. This is why I've started looking for models, like the Street Bowie and Chief, with no thumb ramp. If there is a thumb ramp on a knife, I can pretty much guarantee it will interfere in some grips, even on my beloved Police.
I enjoy designs with no thumb ramp so much more. When I choke up on my Police using the index choil I have to put my thumb on the spine of the blade further down than I find comfortable, because the thumb ramp is in my way.
Seeing photos of people using index choils while using thumb ramps makes me cringe. It looks incredibly uncomfortable and I don't know how folks do it. It kills the first joint on my thumb if I cut anything tougher than a piece of string in that grip.
On the Police I can scoot my hand back a bit while using the choil and thumb ramp to extend that first thumb joint, but most Spydercos don't have enough handle real estate to do that. I can't comfortably use a lil native, delica, dragonfly, urban, etc. for that reason alone.