The anticonvulsant activities of intraperitoneally (IP) given carbamazepine (CBZ) or diphenylhydantoin (DPH), expressed as their respective ED50 values in mg/kg, were assessed after caffeine (CAFF) treatment against maximal electroshock-induced seizures in mice. CAFF was administered IP either in a single dose or every 12 h for 3 (subchronic CAFF) and 14 days (chronic CAFF). Moreover, the protective activity of the antiepileptics was determined in mice which, following chronic CAFF, received a challenge dose of CAFF after either 24 or 72 h since CAFF withdrawal. A significant reduction of the protective efficacy of CBZ was observed after chronic CAFF treatment (in a dose of 11.55 mg/kg), while a single dose and a 3-day treatment did not alter the action of CBZ. In case of CAFF (23.1 mg/kg), a significant elevation of CBZ's ED50 value was noted after 3- and 14-day treatments with CAFF. In contrast, chronic CAFF (23.1-46.2 mg/kg) decreased the anticonvulsive activity of DPH to the same extent as did acute CAFF. Moreover the ED50 values for both, CBZ and DPH, evaluated 24 h after a 14-day treatment with CAFF (in doses of 23.1 and 46.2 mg/kg, respectively), were significantly elevated compared to respective control groups. A strong impairment of the anticon-vulsant action of CBZ and DPH was observed when a challenge dose of CAFF was injected following either 24 or 72 h injection-free time. Pharmacokinetic interactions do not seem to explain the obtained results in terms of total plasma levels of the antiepileptics after chronic treatment with CAFF. Our results may suggest that epileptic patients should avoid CAFF-containing beverages and medicines.