- The best pitchers pitch fewer starts, in exchange for starts by a pitcher who isn't as good as the other pitchers in the rotation.
- A 6-man rotation knocks pitchers off their throwing routine/schedule. Off days could cause weeklong waits between starts, or even more days between starts for some pitchers to keep other pitchers on normal days rest.
- A 6-man rotation causes more wear and tear on the bullpen because there's one less reliever to pitch innings. This means that in addition to reducing starts from your best starter, you're forcing some of the worst pitchers on the team (the middle relievers) to pitch more innings. If instead you carry the same amount of relievers, a 6-man rotation causes less depth on the bench because of one less position player. Note: this issue of depth doesn't make as much of a difference during the regular season after September 1st when major-league rosters expand to 40.
- A 6-man rotation causes an artificial demand for a starter. Starting pitching is one of the toughest areas to acquire depth on your team. If a starter gets injured or if there's a doubleheader because of a rainout earlier in the season, you need more depth on the team to have a 7th man make a spot start to keep the others on schedule than to have a 6th man make a spot start in a 5-man rotation. If your counter to that is to go to a 5-man rotation when a starter of a 6-man rotation gets injured, you're causing another example of the first sentence of reason #2.
- Starting pitchers would likely be less willing to sign incentive-laden clauses if they know they're going to a team with a 6-man rotation because they would know it would be tougher to hit incentives such as innings pitched or games played. Signing players with incentive-laden clauses allows more payroll flexibility when players get hurt.
Yes, I understand the potential benefits of an extra day of rest. Yes, I know Dice-K pitched on 6-man rotations in Japan. Most pitchers aren't used to a 6-man rotation. The cons still outweigh the pros.