Previous analyses of fibrate safety may have been driven by a higher propensity for gemfibrozil to interact with cerivastatin, which is currently off the market because of safety concerns. We reviewed gemfibrozil- and fenofibrate-associated adverse event reports (AERs) submitted to the US Food and Drug Administration over a 5-year period. To control for cerivastatin's impact on fibrate-associated AERs, reports with concomitant cerivastatin use were excluded. Rates per million prescriptions were calculated for all AERs, serious AERs, rhabdomyolysis AERs, muscle-related AERs without rhabdomyolysis, and liver AERs. The rates of all AERs (odds ratio [OR] 0.76, 95% confidence interval [CI] 0.69 to 0.83), serious AERs (OR 0.72, 95% CI 0.65 to 0.81), and liver AERs (OR 0.37, 95% CI 0.28 to 0.50) were significantly lower for gemfibrozil compared with fenofibrate (p <0.001 for each). In contrast, rates of rhabdomyolysis AERs (OR 2.67, 95% CI 2.11 to 3.39, p <0.001) and muscle-related AERs without rhabdomyolysis (OR 1.36, 95% CI 1.12 to 1.71, p = 0.002) were significantly higher for gemfibrozil compared with fenofibrate. In conclusion, the safety profiles of fibrates differ, with a higher rate of liver-related AERs associated with fenofibrate and a higher rate of muscle-related AERs associated with gemfibrozil. Rates of all AERs and serious AERs were higher with fenofibrate, but well within the range observed with commonly used lipid-altering medications.