We describe a sensitive and precise high-pressure liquid chromatographic method in which acetoacetanilide is used as the internal standard to simultaneously determine acetaminophen and phenacetin in plasma. Therapeutic as well as toxic concentrations can be determined on as little as 0.1 ml of plasma. Sample preparation is rapid and chromatography is complete in 5 min. Quantitation is accurate at 0.5 mg/liter concentration for both drugs. Day-to-day precision within 5% is attainable. Of 36 other drugs tested, only theophylline interfered, with the determination of acetaminophen.