This study assessed the effects of fenofibrate on lipoprotein levels and lipoprotein compositions in a subgroup of patients who participated in a multicenter fenofibrate study. Eleven men and 10 women aged 29 to 63 were studied, 12 with type II A and nine with type II B hyperlipoproteinemia. Fasting blood samples were obtained every four to six weeks. Lipoprotein lipids were quantified by procedures of the Lipid Research Clinics, and apolipoproteins by radioimmunoassay. Fenofibrate decreased mean triglyceride and cholesterol levels of the type II A patients from 130 to 99 and from 286 to 237 mg/dl, respectively. Levels of very low-density lipoprotein triglycerides, low-density lipoprotein cholesterol, and very low-density lipoprotein cholesterol decreased and high-density lipoprotein cholesterol levels rose. Apolipoprotein B and apolipoprotein E levels decreased, whereas apolipoprotein AI and apolipoprotein All levels rose. The mean very low-density lipoprotein cholesterol:very low-density lipoprotein triglyceride ratio and low-density lipoprotein cholesterol:low-density lipoprotein triglyceride ratio decreased. The low-density lipoprotein cholesterol:apolipoprotein B ratio and high-density lipoprotein cholesterol:apolipoprotein All ratio decreased as did the apolipoprotein AI:apolipoprotein AII ratio. In patients with type II B hyperlipoproteinemia, triglyceride and cholesterol levels decreased with fenofibrate therapy with most of the decrease in triglyceride levels due to very low-density lipoprotein triglycerides, whereas the decrease in total cholesterol levels was due to decreases in very low-density lipoprotein and low-density lipoprotein cholesterol. High-density lipoprotein cholesterol levels rose. The decrease in low-density lipoprotein cholesterol levels was not significant in this group. Apolipoprotein E levels decreased and apolipoprotein AI and apolipoprotein AII levels rose. Indices of composition in type II B patients were similar to those in type II A patients but the changes were less dramatic. Very low-density lipoprotein cholesterol:very low-density lipoprotein triglyceride ratios decreased significantly, but low-density lipoprotein cholesterol:low-density lipoprotein triglyceride ratios did not change significantly with treatment. The mean low-density lipoprotein cholesterol:apolipoprotein B ratio, high-density lipoprotein cholesterol: apolipoprotein AII ratio, and apolipoprotein AI:apolipoprotein AII ratio all were lowered by therapy. Thus, very low-density lipoprotein and low-density lipoprotein lost cholesterol in response to fenofibrate therapy and high-density lipoprotein particles became enriched in cholesterol.