We describe a determination of zomepirac concentration in plasma and serum by reversed-phase "high-performance" liquid chromatography. The assay requires 1.0 mL of sample and involves diethyl ether extraction of zomepirac from an acidified sample, followed by concentration and injection into a liquid chromatograph. The column effluent is monitored at 330 nm. Retention times of zomepirac and the internal standard (tolmetin) are 3.8 and 2.7 min, respectively. The lower limit of detection for zomepirac in serum or plasma is 0.05 mg/L. Within-day precision (CV) of analysis in plasma or serum with zomepirac added (0.1-10.0 mg/L) ranged from 1.4 to 6.7%; between-day CV varied from 1.4 to 7.5%. Analytical recovery of zomepirac (1.0 mg/L) from serum and plasma was 77.6 (SD 3.5)% and 80.4 (SD 5.2)%, respectively. Numerous commonly coadministered drugs did not interfere. The elimination half-life of the drug was 1.8 h, and the peak plasma concentration ranged from 1.1 to 2.4 mg/L. Peak and trough concentrations measured throughout five days of therapy imply no accumulation.