Eight subjects were studied in a randomized crossover design to determine the effect of aluminum-magnesium hydroxide (AMH), calcium carbonate (CC), and aluminum hydroxide-magnesium trisilicate (AHMT) on the bioavailability of a single, 600-mg dose of phenytoin administered orally. Each subject received phenytoin alone on two separate occasions and phenytoin plus each of the three antacids on three other occasions. Each antacid was administered as 160 mEq at 1 and 3 hr after each meal and at bedtime on the day phenytoin was given. The mean area under the curve (AUC) was significantly decreased by AMH (p < 0.005) and CC (p < 0.05). AHMT had a similar trend but did not reach statistical significance (p = 0.1). Large inter and intrasubject variability in AUC was observed when phenytoin was administered alone. In two subjects, cumulative urinary 5-(4-hydroxyphenyI)-5-phenylhydantoin at 72 hr (HPPH72) was determined. The amount of HPPH recovered had similar trends as the AUC with antacid treatments but not the same magnitude. In this study, antacids altered not only the extent of absorption but also appeared to alter the rate of absorption. Antacids administered in a peptic ulcer regimen may decrease the AUC of a single dose of phenytoin. Patients should be cautioned against concomitant use of antacids and phenytoin.