Insulin resistance syndrome (IRS), high blood pressure, elevated blood glucose and triacylglycerol-rich lipoproteins (TG-RL), as well as low levels of high-density lipoprotein (HDL-C) are disorders that combine to define metabolic syndrome (MetS). Metabolic syndrome is on the rise in the United States and is believed to be a powerful predictor of risk for diabetes and coronary events. Modulation of the activity of lipoprotein lipase (LPL) in MetS affects lipolysis of TG-RL, which has a direct correlation with the levels of plasma HDL-C. This study examined if increasing LPL activity by dietary means in a model for MetS leads to reduced IRS and increase in plasma HDL-C concentration. Ninety day-old Spontaneously Hypertensive Stroke-Prone male rats were originally fed lab chow diet for seven days. This was followed by feeding a fatty acid diet for 7 days containing one of the following: triolein (TO), trans fatty acids-rich (TFA, margarine) and 0 fatty acids (Control) with /without an LPL-rising drug (NO-1866) by gavages (5 mg or 25 mg/kg b. wt.). The results show that blood glucose and triacylglycerol levels were decreased with NO-1886. HDL-C levels increased with NO-1866 in the control and triolein group but not in the TFA group. Animals in the triolein group had higher levels of phospholipids and lower levels of insulin. Inclusion of NO-1866 lowered HOMA-IR by almost 40% in the control and the TFA group, but no further reduction was observed in the TO group. The control TFA groups had up to 45% higher HOMA-IR than the TO group. Overall the data suggest that raising the activity of lipoprotein lipase by dietary means, including the feeding of monounsaturated fat may increase HDL-C, reduce plasma triacylglycerol and other indices of MetS risk, and thus may decrease the incidence of vascular complications through the normalization of lipid metabolism in subjects with MetS.