One hundred and eight Wistar rats were injected with serotonin (20 mg per kilogram of body weight intraperitoneally) or imipramine hydrochloride (20 mg per kilogram intraperitoneally), or both, in a single cycle or in multiple (up to 18 weeks) weekly cycles. In contrast to previous reports, a characteristic myopathy was produced with serotonin alone, identical to that produced by serotonin and imipramine in combination. Imipramine alone produced no significant change. The myopathy produced was characterized by (1) preferential damage to myofibers with high oxidative capacity (types I and IIA), (2) prominent regenerative activity occurring as early as 48 hours, and (3) degeneratio of capillary endothelium (thickening, vacuolar degeneration, proliferation of marginal folds, dissolution of mitochondria). Small groups of degenerating fibers and increased connective tissue were not observed. There was no loss of myofibers or fat replacement. The changes suggested repeated acute insults followed the complete recovery. These observations suggest that although the pathogenesis of serotonin and serotonin-imipramine myopathy is primarily ischemic, it is not a satisfactory model of human Duchenne muscular dystrophy.