This study of 12 patients with mild-to-moderate hypertriglyceridemia compares the mechanisms of triglyceride (TG) lowering by caloric restriction and by clofibrate. Turnover rates of very low density lipoprotein triglycerides (VLDL-TG) were determined by using 3H-glycerol as a precursor. Radioactivity-time curves of VLDL-TG were analyzed with a multicompartmental model. Hypertriglyceridemia in these patients was due mainly to overproduction of VLDL-TG. Clofibrate therapy for 1 month had a variable effect on VLDL-TG levels. A group of relatively poor responders to the drug had a mild increase in the fractional catabolic rate (FCR) of VLDL-TG, but no change in production rates. The remaining patients were relatively good responders; they had increased FCR and modest reductions in synthetic rates of VLDL-TG. However, clofibrate largely failed to correct the primary defect in this group of patients, namely, the overproduction of VLDL-TG. Almost all patients responded to 1 month of caloric restriction (1000 cal/day) with marked reductions in VLDL-TG levels. The major response to reduced caloric intake was a decrease in production of VLDL-TG, although FCR was also increased to some extent. Despite these differences in mechanisms for VLDL-TG lowering, both regimens tended to raise levels of LDL and HDL.