The goal of the present study was to examine the effect of cimetidine, a histamine type 2 receptor antagonist given alone or together with one of the conventional antiepileptic drugs, carbamazepine, phenytoin, phenobarbital or valproate on the exploratory and spontaneous activity in mice after 1 or 7 days of experiment. Animal activity was registered electronically with the use of Digiscan analyzer in relation to ambulatory and rearing activities, as well as total distance travelled by animals in 15 minute periods. Results showed that cimetidine given alone significantly decreased three variables of spontaneous motor activity (horizontal activity, total distance and vertical activity) in mice after single administration. Moreover, cimetidine co-administered with valproate (1 or 7 days), carbamazepine (1 day), phenytoin (1 day) or phenobarbital (7 days) significantly worsened spontaneous activity in mice. Likewise, impairment in horizontal and vertical explorative activity in mice was observed when cimetidine was injected with phenobarbital (1 day), carbamazepine (1 day), valproate (1 or 7 days) and phenytoin (1 day). It could be concluded that cimetidine has deleterious effect on locomotor activity of mice, especially in combination with the antiepileptic agents tested. Further studies are needed to elucidate the influence of cimetidine on patients with epilepsy.