The purpose of this study was to determine whether aspirin or acetaminophen would significantly reduce delayed onset muscle soreness (DOMS) and blood levels of creatine kinase (CK), a marker of muscle tissue damage, after an unaccustomed bout of, eccentric exercise. Thirty‐six untrained men were randomly assigned to an aspirin (3.0 g/day), acetaminophen (3.0 g/day), or placebo group in a double‐blind fashion. Drug or placebo administration began 48 hours before exercise and continued to 72 hours after exercise. Each subject performed the eccentric phase of a supine bench press at a resistance equivalent to 120% of maximum concentric strength, 1 RM (4 sets, 12 repetitions/set). A subjective sensation score of DOMS (1 = normal, 10 = very sore) and serum CK activity were measured before and at 24, 48, 72, 96, and 120 hours after exercise, using a repeated measures ANOVA. No significant group differences (p>0.05) were found in perception of soreness; a significant time effect was observed (p0.05). Serum aspirin and acetaminophen concentrations, assessed before exercise and at 48 hours after, were each within the therapeutic range. These results indicate that administration of aspirin and acetaminophen does not reduce the DOMS and CK response to eccentric exercise.