Thirteen patients with phenotypic type V hyperlipidemia were treated with either gemfibrozil (Lopid) or a placebo in a randomized, double-blind, crossover study for two 8-week periods. A 4-week baseline period of a low-fat diet preceded the study and served as a dietary control period. A 4-week washout period followed the two 8-week periods. Compared with the placebo phase, gemfibrozil produced a significant reduction in the concentrations of total plasma triglycerides (21.03 vs 5.50 mmol/L) and very low-density lipoprotein triglycerides (14.40 vs 4.59 mmol/L) as well as in total plasma cholesterol levels (10.88 vs 5.62 mmol/L) and very low-density lipoprotein cholesterol (6.66 vs 2.15 mmol/L). Chylomicronemia was virtually abolished by the drug treatment. As expected in treated patients with type V hyperlipidemia, concentrations of low-density lipoprotein cholesterol rose after therapy with gemfibrozil (3.08 mmol/L) as compared with placebo (1.84 mmol/L); high-density lipoprotein cholesterol also increased (0.85 mmol/L after therapy with gemfibrozil, 0.62 mmol/L after placebo). The previously very low values for both of these lipoproteins increased at the same time that the total plasma cholesterol value decreased. We conclude that gemfibrozil is a well-tolerated and effective hypolipidemic agent for the treatment of patients with severe hypertriglyceridemia when used in conjunction with a low-fat diet.