The effect of short term (7 days) and long term (28 days) pretreatment with the imidazole H,-receptor antagonist, cimetidine (CMT), on the pharmacokinetics of 5-fluorouracil (5-FUra) has been studied in the rat and cynomolgus monkey. Short-term pretreatment of rats with CMT significantly increased by 29 per cent and AUC by 40 per cent: total body clearance was decreased by 30 per cent. Long-term pretreatment exaggerated these effects. By contrast, short-and long-term pretreatment with the furan H,-receptor antagonist, ranitidine, caused no significant effect on 5-FUra kinetics. In the monkey, 7 days pretreatment with CMT increased t1,2,z by 32 per cent leaving other 5-FUra kinetic parameters unchanged; 28 days pretreatment increased both tl,2.z by 41 per cent and AUC by 100 per cent with a decrease in total body clearance of 5-FUra of 48 per cent. CMT, but not RNT, inhibited cytosolic dihydropyrimidine dehydrogenase (DPD), the enzyme responsible for 5-FUra catabolism. It is proposed that the observed effects of CMT on 5-FUra kinetics are the result of inhibition of DPD. This interaction has the potential for increasing systemic drug toxicity and it is therefore advisable that where H,-receptor blockade is administered concurrently with 5-FUra that a nonimidazole based H,-receptor antagonist such as RNT should be substituted for CMT.