Introduction and objectives: The aim of the study was to asses the impact of long-term therapy with the second generation antiepileptic drug levetiracetam (LEV) with arachidonyl-2’-chloroethylamide (ACEA), a highly selective cannabinoid CB1 receptor agoniston the process of neurogenesis in a mouse pilocarpine model of epilepsy (PILO). Additionally, a relationship was established between the treatment with ACEA in combination with LEV, and hippocampal neurogenesis in mouse PILO brain. Material and methods: All experiments were performed on adolescent male CB57/BL mice injected i.p. with LEV (10 mg/kg), ACEA (10 mg/kg) and PMSF (30 mg/kg) (phenylmethylsulfonyl fluoride — a substance protecting ACEA against degradation by the fatty-acid amidohydrolase), pilocarpine (PILO, a single dose 290 mg/kg) and methylscopolamine (30 min before PILO to stop the peripheral cholinergic effects of the pilocarpine, 1 mg/kg). The process of neurogenesis was evaluated after10 days treatment with LEV and ACEA. Results: Obtained results indicated that the combinations of ACEA+PMSF+LEV and ACEA +PMSF increased the total number of total newborn cells compared to the control. Moreover, ACEA+PMSF administered alone and in combination with LEV had a significant impact on neurogenesis increasing the total number of newborn neurons compared to the control group. Neither LEV nor PMSF had a significant impact on the number of proliferating cells and newborn neurons when compared to the control PILO group. In turn, LEV administered alone decreased significantly the number of astrocytes. However, ACEA+PMSF has demonstrated significant increase of astrocytes compare to control mice. Conclusions: These data provide substantial evidence that the combination of LEV+ACEA significantly increases the level of newborn neurons in the PILO dentate subgranular zone.