AIMS/HYPOTHESIS: Fenofibrate has been noted to cause an elevation in serum creatinine in some individuals. Participants in the Action to Control Cardiovascular Risk in Diabetes Lipid Study were studied to better characterise who is at risk of an increase in creatinine level and to determine whether those with creatinine elevation have a differential risk of adverse renal or cardiovascular outcomes. METHODS: A fenofibrate-associated creatinine increase (FACI) was defined as an increase in serum creatinine of at least 20% from baseline to month 4 in participants assigned to fenofibrate. Baseline patient characteristics, and baseline and 4-month drug, clinical, laboratory characteristics and study outcomes were examined by FACI status. RESULTS: Of the sample, 48% of those randomised to receive fenofibrate had at least a 20% increase in serum creatinine within 4 months. In multivariable analysis, participants who were older, male, used an ACE inhibitor at baseline, used a thiazolidinedione (TZD) at 4 months post-randomisation, had baseline CVD, and had lower baseline serum creatinine and LDL-cholesterol levels were all more likely to meet the criteria for FACI. Participants in the FACI group were also more likely to have a decrease in their serum triacylglycerol level from baseline to 4 months. No differences in study outcomes were seen by FACI criteria. CONCLUSIONS/INTERPRETATION: Several characteristics predict a rapid rise in serum creatinine upon starting fenofibrate. Participants who met the criteria for FACI also had a greater change in triacylglycerol levels. In the setting of careful renal function surveillance and reduction of fenofibrate dose as indicated, no increase in renal disease or cardiovascular outcome was seen in those individuals demonstrating FACI. TRIAL REGISTRATION: ClincalTrials.gov: NCT00000620. FUNDING: The ACCORD Trial was supported by grants (N01-HC-95178, N01-HC-95179, N01-HC-95180, N01-HC-95181, N01-HC-95182, N01-HC-95183, N01-HC-95184, IAA-Y1-HC-9035 and IAA-Y1-HC-1010) from the National Heart, Lung, and Blood Institute; by the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute on Aging, and the National Eye Institute; by the Centers for Disease Control and Prevention; by General Clinical Research Centers and by the Clinical and Translational Science Awards. Abbott Laboratories, Amylin Pharmaceutical, AstraZeneca Pharmaceuticals LP, Bayer HealthCare LLC, Closer Healthcare, GlaxoSmithKline Pharmaceuticals, King Pharmaceuticals, Merck, Novartis Pharmaceuticals, Novo Nordisk, Omron Healthcare, sanofi-aventis US and Takeda Pharmaceuticals provided study medications, equipment or supplies.