My first playthru was strange. I found the moonlit butterfly to be the first truly challenging boss because I was more or less at the mercy of the projectile attacks flung at me. I also had no concept of where to go and so I encountered the butterfly early on in my playthru.

After repeat playthrus, even with summoning help, Quelaag is the first real challenge (because Capra is totally optional). Without fail one of your people always gets killed by the fire burst she makes, or someone forgets (or doesn't know) to bring moss clumps with them to the swamp. Her lava spit makes it hard to approach her and she's basically immune to fire. It's a recipe for disaster unless Mildred is involved.

With summoning, Capra is a cake walk.