Inhibitors of hydroxymethylglutaryl co-enzyme A reductase are widely used to treat hypercholesterolemia. They have a good short- to medium-term safety profile, but long-term safety data are limited. Seven hundred forty-five patients with severe hypercholesterolemia (mean baseline plasma cholesterol level on diet, 9.3 mmol/L [360 mg/dL]) were treated with lovastatin for a median duration of 5.2 years. Their mean age at baseline was 50 years, 68% were male, 60% had familial hypercholesterolemia, and 42% had a history of coronary heart disease. Seventy-seven percent of patients had titrations of lovastatin to 80 mg/d, and 58% took other lipid-lowering agents, usually bile acid sequestrants, concomitantly. The mean changes at 5 years in total, low-density lipoprotein, and high-density lipoprotein cholesterol were -35%, -44%, and +14%, respectively. Eighty percent of patients completed the study, 13% were unavailable for follow-up, 4% were discontinued due to adverse events unlikely to be related to lovastatin, and 3% (21) were discontinued because of drug-attributable adverse events: marked but asymptomatic increase in aminotransferase values (10 patients), gastrointestinal disturbance (three patients), rash (two patients), myalgia (one patient), myopathy (two patients), arthralgia (one patient), insomnia (one patient), and weight gain (one patient). Sixteen patients died during the study, all of coronary disease. Of these, 14 had coronary heart disease at baseline. There were no deaths attributable to trauma, suicide, or homicide, and there were only 14 cases of cancer (vs 21 expected). There was no evidence for an adverse effect on the lens. Lovastatin is a generally well-tolerated and effective drug during long-term use.