The effects of chronic administration of aminophylline (AMPH; 50 mg/kg, twice daily for 14 consecutive days) were studied on both antielectroshock efficacy of diazepam (DZP) and convulsive activity of AMPH in mice. AMPH injected acutely at a dose of 50 mg/kg significantly reduced anticonvulsant action of DZP elevating ED50 from 10.9 (control) to 15.9 mg/kg (p < 0.01). After the administration of AMPH for 3 days, ED50 value was still higher compared with control. Chronic treatment with AMPH resulted in further increase of ED50 of DZP, which was 20.2 mg/kg, and this elevation was significant not only when compared with saline-treated animals, but also with acute and 3-day administration of the xanthine (p < 0.01, 0.05, and 0.001, respectively). Therefore, no tolerance to this AMPH-mediated effect was found, and even an enhancing influence was observed. On the other hand, chronic treatment with AMPH decreased convulsive activity of AMPH elevating ED50 for induction of clonic seizures from 218 to 252 mg/kg (p < 0.01). The remaining seizure parameters were unaffected. Furthermore, in both cases pharmacokinetic interactions were excluded, at least in terms of total plasma levels of the drugs. The results suggest that the mechanisms governing AMPH-induced reversal of the anticonvulsant efficacy of DZP qualitatively differ from those underlying AMPH-induced convulsions. Moreover, these data support the claim that AMPH should be avoided in patients suffering from different types of epilepsy.