There were marked individual differences in the plasma levels of phenacetin after oral administration of a 900-mg dose to 9 normal volunteers eating customary home diet. Feeding a diet that contained charcoal-broiled beef for 4 days prior to the administration of phenacetin markedly decreased the plasma levels of this drug without appreciably influencing the plasma concentrations of phenacetin's metabolite, N-acetyl-p-aminophenol (APAP), or the plasma half-life of phenacetin. The average peak concentration of phenacetin in plasma, after a 900-mg oral dose, fell from 1,628 ng/ml, when the subjects were fed a control diet for 7 days, to 352 ng/ml after they were fed the same diet which contained charcoal-broiled beef for 4 days. The average peak concentration of phenacetin rose to 1,885 ng/ml after the subjects were subsequently fed the control diet for 7 days. The ratios of the average concentrations of APAP in plasma to those of phenacetin markedly increased after the charcoal-broiled beef diet. The results suggest that a diet containing charcoal-broiled beef enhances the metabolism of phenacetin in the gastrointestinal tract and/or during its first pass through the liver. This effect greatly decreases the bioavailability of phenacetin.