1. A randomized, double-blind, placebo-controlled trial utilizing creatine as a potential lipid-lowering agent was conducted to determine plasma lipid, lipoprotein, glucose, urea nitrogen and creatinine profiles in men and women ranging in age from 32 to 70 years. 2. Thirty-four subjects (18 men and 16 women) with total cholesterol concentrations exceeding 200 mg/dl received either a creatine supplement (5 g of creatine plus 1 g of glucose) or a glucose placebo (6 g of glucose) for 56 days. Creatine and placebo were taken orally four times a day for 5 days and then twice a day for 51 days. Plasma analyses were measured at baseline, 4 and 8 weeks of treatment, and at 4 weeks after cessation of treatment (week 12). 3. Significant reductions in plasma total cholesterol, triacylglycerols and very-low-density lipoprotein-C occurred within the creatine monohydrate group. Minor reductions in plasma total cholesterol from baseline (233 +/- 9 mg/dl) of 6% and 5% occurred at weeks 4 and 8, respectively, before returning to baseline at week 12. Baseline triacylglycerols (194 +/- 21 mg/dl) and very-low-density lipoprotein-C (39 +/- 4 mg/dl) were reduced by 23% and 22% at weeks 4 and 8, respectively, and remained attenuated by 26% at week 12. These results remained consistent when data were separated and analysed by gender. Finally, a small, but statistically significant increase in urea nitrogen was observed in women between baseline (11.8 +/- 0.7 mg/dl) and week 8 (13.8 +/- 0.7 mg/dl, P < 0.05). No significant differences were noted for low-density lipoprotein-C, high-density lipoprotein-C, total cholesterol/high-density lipoprotein ratio, glucose, creatinine, body mass, body mass index or physical activity within or between the experimental and placebo groups. However, a trend towards reduced blood glucose levels was present in males given creatine monohydrate (P = 0.051). 4. These preliminary data suggest that creatine monohydrate may modulate lipid metabolism in certain individuals. These observations may demonstrate practical efficacy to the hyperlipidaemic patient as well as providing possible new mechanistic insights into the cellular regulation of blood lipid concentrations.