Seat pain is common among amateur bicyclists, who often self‐treat seat pain with skin creams. This research evaluates the efficacy of two commonly used creams, compared with a placebo, for preventing bicycle‐related seat pain. Studied were 188 adults participating in a 500 mile, week‐long amateur bicycle trip. Participants were randomly allocated to receive 0.5% hydrocortisone cream, 10% trolamine salicylate cream, or a nonmedicated placebo cream, in a double‐blind fashion. Each cyclist applied cream to his seat area skin twice daily. After the ride, cyclists were evaluated to determine severity of their seat pain and presence of skin breakdown. The data were analyzed to determine if these outcomes differed among the three groups. Overall, 84.9% of the participants experienced seat pain and 6.9% had seat area skin breakdown, but there were no significant differences among the three cream groups. These results show that hydrocortisone (0.5%) or trolamine salicylate (10%) creams are no more effective than placebo for preventing bicycle‐related seat pain.