Procainamide and cimetidine are eliminated in large part by the kidneys. Both are secreted by an active transport mechanism in the proximal tubule and each inhibits secretion of the other in the isolated, perfused rabbit tubule. In this study in man, cimetidine inhibited renal clearance of oral procainamide by 36%. This was associated with a 28% decrease in the ratio of systemic clearance of procainamide to bioavailability, an 18% decrease in the elimination rate constant, and a 24% prolongation of elimination t1/2. These results suggest that cimetidine increases plasma t1/2 and decreases systemic clearance of procainamide in part by inhibiting its active secretion by the kidneys.