To determine whether changes in plasma lipids following a weight loss program were related to modifications in gene expression of the LDL receptor (LDL-R), lipoprotein lipase (LPL), and 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase, overweight/obese premenopausal women were recruited. The 10-wk, randomized, double-blind intervention consisted of a hypoenergetic diet, high in protein (30% energy) and low in carbohydrate (40% energy), increased physical activity (number of steps taken per day), and intake of a supplement (carnitine or placebo). Our initial hypothesis was that carnitine would enhance the beneficial effects of weight loss on plasma lipids and anthropometrics. Because the carnitine and placebo groups did not differ in any of the measured variables, data for all subjects were pooled and comparisons were made between baseline and postintervention. Mean weight loss was 4.4 kg (P < 0.001), and plasma triglycerides (TG), total, and LDL cholesterol (LDL-C) were reduced by 31.8, 9.9, and 11.9%, respectively (P < 0.001). The expression of the genes of interest was measured in RNA extracted from mononuclear cells at baseline and postintervention using a semiquantitative RT-PCR method. Glyceraldehyde-3-phosphate dehydrogenase was used as an internal control. After 10 wk, there was a 25.7% increase in the abundance of LPL mRNA (P < 0.01) and a 27.7% increase in that of LDL-R mRNA (P < 0.01). The expression of HMG-CoA reductase was not altered by weight loss. The results suggest that the increased expression of the LDL-R and LPL after the intervention might have contributed to the lower plasma LDL-C and TG observed in these women.