The 3-years efficacy and safety of the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor simvastatin (S) (previously called synvinolin or MK-733) has been studied in single and combined therapy with cholestyramine (C) in 48 hypercholesterolaemic patients. Plasma lipids, lipoproteins and apolipoproteins A-I and B, and blood safety tests (haematology, liver function, creatine phosphokinase (CPK), creatinine, blood glucose and thyroid function) were determined regularly throughout the study. Extensive ophthalmological examinations with particular focus on the lens were done before initiation of therapy and at every 6 months during drug treatment. Maximal reductions of mean plasma total cholesterol concentration (34% with S; 47% with S + C) and low-density lipoprotein (LDL)-cholesterol concentration (42% with S; 56% with S + C) were achieved after 4 weeks on full-dose therapy. During continued treatment, years 1 through 3, the reduction of mean plasma total cholesterol was 26-29% with S alone, and 31-41% with S + C. Significant reductions of plasma triglycerides (15-27%) and very low density lipoprotein (VLDL) triglycerides (10-27%) were achieved in the group treated with S as single therapy. In this group there was also a significant increase (10-14%) of high-density lipoprotein (HDL)-cholesterol. In liver aspartate (AST) and alanine (ALT) aminotransferases, as well as alkaline phosphatase (ALP), minor and variable, but usually transient, increases were seen. Repeated ophthalmological examinations did not demonstrate any drug-related side effects. It is concluded that simvastatin is a safe and efficient cholesterol-lowering drug for long-term therapy, both as a single drug and in combination with cholestyramine.