Hypercholesterolaemia is a chronic condition that often requires life-long treatment, making the safety of lipid-lowering drugs a critical issue. 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors ('statins') are commonly used as the pharmacotherapeutic treatment of choice for patients with hypercholesterolaemia. These agents have consistently demonstrated a positive safety and tolerability profile, and are recommended by the US National Cholesterol Education Program guidelines and by the European Joint Task Force for Prevention of Coronary Heart Disease to be used after, or in addition to, a first-line approach with diet. Several large-scale clinical trials have shown HMG-CoA reductase inhibitors to be efficacious and well tolerated, and to be associated with a low rate of treatment withdrawal due to adverse events. These studies included mortality and morbidity end-points, and comprised both primary- and secondary-prevention trials. Hepatic, renal and muscular systems are rarely affected during HMG-CoA reductase inhibitor therapy and the few drug interactions that can occur with concomitantly administered drugs are well documented. There is no conclusive evidence linking HMG-CoA reductase inhibitors to the development of cancer in humans. In long term studies with various HMG-CoA reductase inhibitors, there was no increase in cancer rates compared with placebo. Thus, it can be concluded that HMG-CoA reductase inhibitors are well tolerated, effective treatments for hypercholesterolaemia.