Background: Fenofibrate lowers serum total cholesterol and triglyceride levels while it elevates serum high-density lipoprotein cholesterol (HDL-C) level. Objective: The aim of this study was to investigate the effects of fenofibrate on the particle size of high-density lipoprotein (HDL). Methods: Patients with hyperlipidemia (as defined by serum triglyceride level ≥150 mg/dL in the fasting state) were enrolled in this randomized, double-blind, placebo-controlled, multicenter, crossover study. Fenofibrate 300 mg (corresponding to 200 mg of micronized fenofibrate) or placebo was administered orally once daily after dinner for 8 weeks, followed by crossover of the 2 drugs for an additional 8 weeks. Results: Fifty hyperlipidemic patients (31 men, 19 women; mean [SD] age, 54.6 [12.7] years) were enrolled. Serum total cholesterol and triglyceride levels were significantly reduced with fenofibrate treatment compared with placebo (9.4% [ P = 0.007] and 34.4% [ P < 0.001], respectively), whereas HDL-C levels were significantly elevated (by 25.8% [ P < 0.001]). Lipoprotein lipase (LPL) activity, LPL protein level, and hepatic triglyceride lipase activity increased by 10.5%, 13.4%, and 11.4%, respectively, with fenofibrate compared with placebo. HDL was classified into 3 groups by particle size: HDL 3 <88 Å; HDL 2 a ≥88 Å but <98 Å; and HDL 2 b ≥98 Å. The amount of HDL 3 increased significantly with fenofibrate compared with placebo ( P < 0.001). Fenofibrate was well tolerated during the study. Abnormal clinical laboratory values were noted in 20 of 48 patients (41.7%), but these events were mild and not clinically significant. Conclusion: Taken together, these findings indicate that fenofibrate therapy increased the HDL subfraction with the smallest diameter (HDL 3), which is largely responsible for withdrawing cholesterol from peripheral cells.