No monotherapy is able to tackle effectively all atherogenic features of familial combined hyperlipidemia: high low-density lipoprotein (LDL) cholesterol, triglycerides (TG), and plasma fibrinogen, as well as low high-density lipoprotein (HDL) cholesterol. The present study investigated the safety and efficacy of combined pravastotin or simvastatin with gemfibrozil or ciprofibrate treatment on total cholesterol, LDL, TG, plasma fibrinogen, and apoproteins B and A-I in patients with refractory familial combined hyperlipidemia, with or without coronary artery disease. From the initial 420 patients included in the study, 389 (294 men and 95 women, mean age 51 years [range 30 to 65]) completed the study. These patients were followed for a mean period of 29 months (1 year [n = 107], 2 years [n = 102], 3 years [n = 95], and 4 years [n = 85]). Patients given a hypolipidemic diet were randomly assigned to pravastatin + gemfibrozil (n = 135, 20 and 1,200 mg/day, respectively), simvastatin + gemfibrozil (n = 130, 20 and 1,200 mg), or simvastotin + ciprofibrate (n = 124, 20 and 100 mg). Lipid parameters, apoproteins B and A-I, and plasma fibrinogen were assessed every 3 months. Physical and laboratory investigations for adverse effects were performed every month for the first 3 months and every 3 months thereafter. No patient exhibited myopathy or rhabdomyolysis. Five patients (1.3%) were withdrawn from the study because of high transaminases (more than threefold the upper normal limit). Five nonfatal coronary artery disease events were recorded. All 3 combination treatments were more effective in normalizing lipid profile than any monotherapy in the past. Simvastatin + ciprofibrate was more effective than pravastatin + gemfibrozil in reducing LDL, TG, and plasma fibrinogen levels. Simvastatin + gemfibrozil increased HDL levels more than the other 2. The apoprotein B decrease was analogous to the LDL reduction by all combinations, whereas apoprotein A-I was increased more with simvastatin + gemfibrozil. The data suggest that the statin-fibrate combinations used in the study are safe and have a favorable effect on all major coronary artery disease risk factors in patients with refractory familial combined hyperlipidemia with or without coronary artery disease. Early detection of the rare drug-induced reversible hepatotoxicity calls for close monitoring of patients.