L-Carnitine has been reported to have beneficial effects in the reduction of serum triglycerides and increases high-density lipoprotein cholesterol in hemodialysis patients. The published reports are, however, equivocal. Paradoxical increases in serum triglycerides following intravenous administration of L-carnitine have been observed. It has been suggested that the paradoxical rise in triglycerides may result from the high doses used and intravenous administration, both of which may cause abnormally high tissue concentrations. In the present study 22 hemodialysis patients were selected. All patients had been treated intravenously with 2 g of L-carnitine administered at the end of dialysis for a minimum of 12 months. Treatment with L-carnitine was then discontinued during a 4-month washout period. The patients were then divided into two equal subgroups and placed on L-carnitine therapy (1 g i.v.) at the end of dialysis for 1 month. Thereafter, L-carnitine was added to the dialysate (2 g in group 1, 4 g in group 2) for 3 months. Serum and muscle carnitine levels were determined throughout the study as were lipid parameters, serum chemistry, and hematoiogy. Muscle biopsies obtained at baseline revealed supranormal levels of carnitine which decreased to normal levels following the 4-month washout period. When therapy with L-carnitine was resumed, intravenous administration or in dialysate, the muscle carnitine levels remained within the normal range. Similarly, serum carnitine was markedly elevated at baseline and decreased to normal during the washout period. When L-carnitine was added to the dialysate, total carnitine was observed to significantly increase in the group receiving 4 g. No other significant differences in serum carnitine were observed. A progressive worsening of the lipid profile as evidenced by an increase in triglycerides, and a decrease in high-density lipoprotein cholesterol was observed in patients during the 4-month washout period. Treatment with L-carnitine (intravenously and in the dialysate) decreased triglyceride levels and increased high-density lipoprotein cholesterol. No significant differences were observed between the 2-gram and 4-gram doses of L-carnitine added to the dialysate. It is concluded that the therapeutic objectives in the supplementation of hemodialysis patients with L-carnitine may be best achieved with short-term intravenous administration of L-carnitine followed by long-term administration through the dialysate.