Triglycerides are increasingly being recognized as a risk factor for cardiovascular disease. Research efforts to identify sources of variability in triglyceride-lowering response to the lipid-lowering drug fenofibrate require quantification of the active acidic form of this PPAR-alpha agonist. Anion-exchange solid-phase extraction, in combination with reverse-phase high-performance liquid chromatography (HPLC), rapidly and accurately determines steady-state fenofibric acid serum concentrations. Chromatographic separation under isocratic conditions, with use of ultraviolet detection at 285 nm, provides clean baseline and sharp peaks for clofibric acid, 1-napthyl acetic acid (internal standards), and fenofibric acid. Commonly prescribed and over-the-counter nonsteroidal anti-inflammatory drugs (NSAIDs) were screened for assay interference, and the assay was employed to quantify fenofibric acid in more than 800 human subject specimens. Fenofibric acid analysis was found to be linear over the range of 0.5 to 40 mg/L and was validated with either internal standard. Accuracies ranged from 98.65% to 102.4%, whereas the within- and between-day precisions ranged from 1.0% to 2.2% and 2.0% to 6.2%, respectively. NSAIDs had minimal interference with the assay, which succeeded in quantifying fenofibric acid in more than 843 of 846 serum samples from human subjects, many taking a variety of coadministered medications. Anion-exchange solid-phase extraction in combination with reverse-phase HPLC accurately determines steady-state fenofibric acid serum concentrations in humans without interference from NSAIDs or commonly administered medications. This method is suitable for quantification of fenofibric acid for clinical pharmacokinetic studies in patients with dyslipidemia.