Fenofibrate is a potent hypolipemic agent, widely used in patients with renal insufficiency in whom dyslipidemia is frequent. A moderate reversible increase in creatinine plasma levels is an established side effect of fenofibrate therapy, which mechanism remains unknown. We have previously reported that in 13 patients with normal renal function or moderate renal insufficiency, two weeks of fenofibrate therapy increased creatininemia without any changes in renal plasma flow and glomerular filtration rate [<citeref rid="ref001">1</citeref>]. In 13 additional patients, muscular enzymes (AST, GPT, CPK, LDH) and myoglobin were measured before and after 2 weeks on fenofibrate, and the values of creatininemia obtained by the Jaffé technique and HPLC were compared. CPK and AST activity and plasma myoglobin increased in 2 patients with fenofibrate, but muscular enzymes remained unchanged in the population as a whole, and were not correlated to the changes in creatininemia. The changes in creatininemia induced by fenofibrate measured by the Jaffé technique were strongly correlated to those measured by HPLC (r<sup>2</sup> = 0.675, p = 0.0006). Analysis of the pooled data of the two arms of the study showed in 26 patients that two weeks of fenofibrate therapy efficiently reduced total cholesterol and triglycerides plasma levels, and raised creatininemia from 139 ± 8 to 160 ± 10 µmol/l (p < 0.0001), but confirmed that creatininuria also increased to the extent that creatinine clearance remained unchanged (68 ± 6 vs. 67 ± 6 ml/min, n.s.). It is concluded that the increase in creatininemia induced by fenofibrate in renal patients does not reflect an impairment of renal function, nor an alteration of tubular creatinine secretion, and is not falsely increased by a dosage interference. Fenofibrate-induced increase of daily creatinine production is neither readily explained by accelerated muscular cell lysis. It is proposed that fenofibrate increases the metabolic production rate of creatinine.