This experiment examined the effect of a moderate dose of caffeine on perceptions of leg-muscle pain during a bout of high-intensity cycling exercise and the role of anxiety sensitivity in the hypoalgesic effect of caffeine on muscle pain during exercise. Sixteen college-age women ingested caffeine (5 mg/kg body weight) or a placebo and 1 hr later completed 30 min of cycling on an ergometer at 80% of peak aerobic capacity. The conditions were completed in a counterbalanced order, and perceptions of leg-muscle pain were recorded during the bouts of exercise. Caffeine resulted in a large reduction in leg-muscle pain-intensity ratings compared with placebo (d = -0.95), and the reduction in leg-muscle pain-intensity ratings was larger in those with lower anxiety-sensitivity scores than those with higher anxiety-sensitivity scores (d = -1.28 based on a difference in difference scores). The results support that caffeine ingestion has a large effect on reducing leg-muscle pain during high-intensity exercise, and the effect is moderated by anxiety sensitivity. © 2008 Human Kinetics, Inc.