Context. - Although cholesterol-reducing treatment has been shown to reduce fatal and nonfatal coronary disease in patients with coronary heart disease (CHD), it is unknown whether benefit from the reduction of low- density lipoprotein cholesterol (LDL-C) in patients without CHD extends to individuals with average serum cholesterol levels, women, and older persons. Objective. - To compare lovastatin with placebo for prevention of the first acute major coronary event in men and women without clinically evident atherosclerotic cardiovascular disease with average total cholesterol (TC) and LDL-C levels and below-average high-density lipoprotein cholesterol (HDL- C) levels. Design. - A randomized, double-blind, placebo-controlled trial. Setting. - Outpatient clinics in Texas. Participants. - A total of 5608 men and 997 women with average TC and LDL-C and below-average HDL-C (as characterized by lipid percentiles for an age- and sex-matched cohort without cardiovascular disease from the National Health and Nutrition Examination Survey [NHANES] III). Mean (SD) TC level was 5.71 (0.54) mmol/L (221  mg/dL) (51st percentile), mean (SD) LDL-C level was 3.89 (0.43) mmol/L (150  mg/dL) (60th percentile), mean (SD) HDL-C level was 0.94 (0.14) mmol/L (36  mg/dL) for men and 1.03 (0.14) mmol/L (40  mg/dL) for women (25th and 16th percentiles, respectively), and median (SD) triglyceride levels were 1.78 (0.86) mmol/L (158  mg/dL) (63rd percentile). Intervention. - Lovastatin (20-40 mg daily) or placebo in addition to a low-saturated fat, low-cholesterol diet. Main Outcome Measures. - First acute major coronary event defined as fatal or nonfatal myocardial infarction, unstable angina, or sudden cardiac death. Results. - After an average follow-up of 5.2 years, lovastatin reduced the incidence of first acute major coronary events (183 vs 116 first events; relative risk [RR], 0.63; 95% confidence interval [Cl], 0.50-0.79; P<.001), myocardial infarction (95 vs 57 myocardial infarctions; RR, 0.60; 95% Cl, 0.43-0.83; P = .002), unstable angina (87 vs 60 first unstable angina events; RR, 0.68; 95% Cl, 0.49-0.95; P = .02), coronary revascularization procedures (157 vs 106 procedures; RR, 0.67; 95% Cl, 0.520.85; P= .001), coronary events (215 vs 163 coronary events; RR, 0.75; 95% Cl, 0.61-0.92; P = .006), and cardiovascular events (255 vs 194 cardiovascular events; RR, 0.75; 95% Cl, 0.62-0.91; P = .003). Lovastatin (20-40 mg daily) reduced LDL-C by 25% to 2.96 mmol/L (115 mg/dL) and increased HDL-C by 6% to 1.02 mmol/L (39 mg/dL). There were no clinically relevant differences in safety parameters between treatment groups. Conclusions. - Lovastatin reduces the risk for the first acute major coronary event in men and women with average TC and LDL-C levels and below-average HDL-C levels. These findings support the inclusion of HDL-C in risk-factor assessment, confirm the benefit of LDL-C reduction to a target goal, and suggest the need for reassessment of the National Cholesterol Education Program guidelines regarding pharmacological intervention.