Objective:To assess the efficacy of simvastatin in a large patient cohort.Design:In an open multicentre study, after a four week placebo phase, patients were treated with simvastatin for 24 weeks; a subgroup continued therapy for a further 24 weeks. Efficacy of simvastatin (a) with prolonged use over three years, and (b) in combination with bezafibrate was assessed in an open single site study.Setting:Lipid or cardiology specialist hospital outpatient clinics.Patients:For the open multicentre study, 228 patients with primary hypercholesterolaemia (total cholesterol level>6.5 mmol/L) were recruited, of whom 224 met entry criteria and completed the study. Forty‐seven of these patients continued therapy for one year. In the open single site study, 22 patients (with low density lipoprotein [LDL] cholesterol levels>4.3 mmol/L) participated in studies of long term use (n= 9) or of combined therapy (n= 13).Intervention:Therapy in the open multicentre study began with 10 mg of simvastatin per day, doubling to 20 mg after six weeks and then 40 mg after 12 weeks of therapy if total cholesterol levels persisted above 5.2 mmol/L. In the study of long term use, simvastatin (40 mg daily) was taken continuously over three years. In the study of combination therapy, bezafibrate (600 mg daily) was taken in addition to simvastatin (40 mg daily) for 10 months.Main outcome measures:Plasma lipid and lipoprotein concentrations.Results:In the multicentre study, total plasma cholesterol levels were reduced by 32.8% from 9.11 ± 1.84 (in mmol/L, mean ± SD) to 6.12 ± 1.25 (P<0.001), and LDL cholesterol levels by 41.4% from 6.90 ± 1.92 to 4.04±0.31 (P<0.001). The effect of therapy was sustained in those patients continuing therapy to 48 weeks. The study of long term use found no significant attenuation of effect over three years of monotherapy. Combined simvastatin/bezafibrate therapy reduced the LDL cholesterol concentration by a further 19.9% (P<0.001) from levels achieved on simvastatin alone.Conclusions:Simvastatin is an effective, well tolerated lipid lowering drug, without significant attenuation of effect with prolonged use. Simvastatin plus bezafibrate appears to be a potentially useful drug combination.