Although an inverse association between triglyceride (TG) and (HDL-C) is well documented, the impact of lowering TG on HDL-C levels has not been well established. Therefore, data were analyzed in 151 consecutive dyslipidemic patients who made multiple visits (n=1830) to the University of Maryland Preventive Cardiology Center between 1991 and 2005. At baseline, fasting TG levels at or above the median (178 mg/dL) were associated with significantly lower HDL-C than TG levels below the median (32.6+/-11.1 mg/dL versus 45.1+/-14.2 mg/dL; P<0.0001). Following baseline evaluation, various therapies were employed (i.e., dietary, exercise, medication) to reduce mean LDL (147.3+/-53.4 mg/dL) and TG (306.1+/-414.9 mg/dL). Using a fully adjusted mixed regression model, each 50 mg/dL reduction in TG was independently associated with a 0.5 mg/dL increase in HDL-C in hypertriglyceridemic subjects (e.g., TG> or =200 mg/dL) and a 1.7 mg/dL increase in HDL-C in the absence of elevated TG (P<0.0001). The use of niacin (P<0.0001), statins (P=0.0003) and fibrates (P=0.03) were also associated with significant increases in HDL-C beyond that anticipated with TG reduction. These data indicate that lowering TG is independently and inversely correlated with HDL-C, effects that are most pronounced in the absence of hypertriglyceridemia.