In 1997, the US Food and Drug Administration (FDA) reported valvular regurgitation (aortic regurgitation [AR] mild or greater and/or mitral regurgitation [MR] moderate or greater) in 32.8% of patients treated with anorexigens. This study sought to determine the natural history of valvular regurgitation in patients who were included in the FDA's original report. This was a nonrandomized, natural history study of these subjects. Cohort I consisted of 155 of 186 patients (83%) who were reported to the FDA. Cohort II consisted of a similar group of 311 patients who were not included. Initial echocardiograms were obtained for medical indications before the study initiation, and study echocardiograms were standardized and obtained at 3-month intervals. Level III echocardiographers performed blinded, side-by-side comparison of the first and last study echocardiograms at a core laboratory. Cohorts I and II consisted of predominantly female, middle-aged, obese subjects. At enrollment, patients in cohorts I and II had mild or greater AR (17.9%, 13.5%) and moderate or greater MR (3.3%, 4.0%), respectively, which was less than in the FDA's report. At follow-up, there were no statistically significant changes in the degree of valvular regurgitation in either cohort when the first and last study echocardiograms were read side by side. In conclusion, this natural history follow-up study demonstrates that MR and AR in long-term anorexigen-treated patients was less than reported to the FDA, did not progress, and remained echocardiographically stable during the 10-month duration of the study.