The weak peroxisome proliferator activated receptor-α (PPAR-α) agonists gemfibrozil and fenofibrate achieve only small increases in high-density lipoprotein (HDL) cholesterol. CP-778,875 is a more potent PPAR-α agonist developed to produce greater HDL cholesterol increases. This randomized, multicenter, double-blinded, placebo-controlled study evaluated the efficacy and safety of CP-778,875 in subjects with mixed dyslipidemia and type 2 diabetes. Eight-six subjects with low HDL cholesterol (≤45 mg/dl for men and ≤55 mg/dl for women) and increased triglycerides (150 to 500 mg/dl) who had coexisting type 2 diabetes were randomized. Subjects received CP-778,875 doses of 0.5, 2, or 6 mg/day or placebo for 6 weeks. Any other lipid-altering therapy was stopped at screening. The primary end point was percent change in HDL cholesterol from baseline. The 2-mg/day dose of CP-778,875 significantly increased HDL cholesterol by 14%. The 2-mg dose also increased concentrations of apolipoprotein (apo) A-I, HDL₂ cholesterol, and HDL₃ cholesterol by 13%, 12%, and 19%, respectively. An unusual dose–response pattern was observed in that at 6 mg/day CP-778,875 only increased HDL cholesterol by 3% and decreased HDL₂ cholesterol by 24%. Fasting triglyceride levels were significantly decreased to a similar extent (26%) by all 3 doses of CP-778,875. CP-778,875 significantly increased homocysteine levels. There was no significant relation between change in homocysteine and change in apoA-I or HDL cholesterol. No subjects developed myopathy. In conclusion, CP-778,875 2 mg/day significantly increased HDL cholesterol, significantly lowered fasting triglycerides, and increased apoA-I and HDL subfractions. The clinical relevance of the increase in homocysteine levels is unknown.