Is your saddle wide enough?
My first bike the second time around was a hybrid -- so my experience may not be relevant. But after the first 6.5 mile ride (practicing my commute), the stock saddle on my Specialized Vita Sport clearly had to go. It was wide: 155 mm -- but not wide enough for me. It was pushing between my sit bones, not supporting them, even though when I sit on a butt-measuring device, it looks like a 155 should fit me. I got a 175 mm saddle of the same model (Specialized Sonoma) which was immediately comfortable for 2 hour rides.
The bike was not comfortable for longer rides, which was partly due to the saddle, and partly due to the geometry. Now I ride a Brooks B-17 with a cut-out on a roadish bike. It never feels like an easy chair, but it feels no worse after 80 miles than it does after 1 mile (100 miles was another matter), and I have never had a problem getting back on the bike the next day.
I have rented another road bike with a more typical roadie saddle, and had very unhappy iscial tuberosities the next day, even though I rode no further on the rented bike than I was used to doing on my own bike.