This study compared the relative efficacy of a once-daily niacin extended-release (ER)/lovastatin fixed-dose combination with standard doses of atorvastatin or simvastatin, with a special emphasis on relative starting doses. Subjects (n = 315) with elevated low-density lipoprotein (LDL) cholesterol and decreased high-density lipoprotein (HDL) cholesterol blood levels (defined as LDL cholesterol blood levels > or =160 mg/dl without coronary artery disease, or > or =130 mg/dl if coronary artery disease was present, and HDL cholesterol <45 mg/dl in men and <50 mg/dl in women) were randomized to atorvastatin, simvastatin, or niacin ER/lovastatin for 16 weeks. The primary efficacy variables were the mean percent change in LDL cholesterol and HDL cholesterol levels from baseline. After 8 weeks, the starting dose niacin ER/lovastatin 1,000/40 mg and the 10-mg starting dose atorvastatin both lowered mean LDL cholesterol by 38%. After 12 weeks, niacin ER/lovastatin 1,000/40 mg lowered LDL cholesterol by 42% versus 34% with the 20-mg starting dose of simvastatin (p <0.001). Niacin ER/lovastatin increased HDL cholesterol significantly more than atorvastatin or simvastatin at all compared doses (p <0.001). Niacin ER/lovastatin also provided significant improvements in triglycerides, lipoprotein(a), apolipoprotein A-1, apolipoprotein B, and HDL subfractions. A total of 6% of study subjects receiving niacin ER/lovastatin withdrew because of flushing. No significant differences were seen among study groups in discontinuance due to elevated liver enzymes. No drug-induced myopathy was observed. Niacin ER/lovastatin was comparable to atorvastatin 10 mg and more effective than simvastatin 20 mg in reducing LDL cholesterol, was more effective in increasing HDL cholesterol than either atorvastatin or simvastatin, and provided greater global improvements in non-HDL cholesterol, triglycerides, and lipoprotein(a).