The effect of low doses of cimetidine on theophylline clearance and metabolism was studied. In a randomized, crossover study, 10 healthy men received oxtriphylline alone or with cimetidine. Oxtriphylline 200 mg (equivalent to theophylline 135 mg) was given orally every eight hours for 10 doses. Cimetidine 300 mg was given orally at bedtime for four days, beginning the same day as oxtriphylline treatment. At least 10 days separated study periods. In each study period, blood samples for plasma theophylline determinations were drawn 24 hours before the last dose of oxtriphylline, at the time of the last dose, and periodically up to 32 hours after the last dose. A 24-hour urine collection for quantification of theophylline and metabolite excretion was started at the time of the last oxtriphylline dose. Plasma theophylline clearance decreased significantly by a mean of 12.2% during cimetidine treatment. Area under the curve showed a significant mean increase of 17.4%. Increases in clearance and area under the curve values occurred in 9 of 10 subjects. In 6 of 10 subjects who had increases in theophylline trough concentrations, the mean increase was 28.2%; when all 10 subjects were considered, however, the mean increase was 10.3%, which was not significant. No significant differences in the urinary recoveries of theophylline or its metabolites were noted between study periods. Because of the decreases in theophylline clearance produced by low doses of cimetidine in this study, clinicians should monitor for potential theophylline toxicity in patients who receive these drugs concomitantly.