1. The anticonvulsant activity of calcium channel antagonists, was studied after intraperitoneal or oral administration in genetically epilepsy prone rats (GEPR). 2. Flunarizine, dihydropyridines and HA 1004, administered intraperitoneally, were the most potent compounds. Diltiazem, prenylamine, perhexiline, verapamil and methoxyverapamil, given intraperitoneally, were able to reduce the incidence of the tonic phase but were completely ineffective in preventing clonic and running phases of sound-induced seizures in GEPR. Similar anticonvulsant activity was observed when these compounds were administered orally. 3. After intracerebroventricular administration of some of the hydrosoluble calcium antagonists studied, the anticonvulsant effects were similar to those observed after systemic administration. 4. The systemic administration of Bay K 8644, a dihydropyridine analogue, having the ability to stimulate calcium entry into cells produced a dose-dependent increase in clonic and tonic convulsions and other epileptic phenomena, which were prevented by pretreatment with nimodipine or nitrendipine. 5. The possible role of purinergic, excitatory amino acid, GABA-benzodiapine mechanisms as well as the role of Ca2(+)-calmodulin and calcium channel binding sites on the anticonvulsant effects of some calcium antagonists are discussed.