Background and Objective: Increasing patients with epilepsy need some form of antidepressant, which trazodone is one of the most widely prescribed. However, the seizure risk of trazodone has not been assessed. The objective of this study is to determine whether trazodone hydrochloride (TH, a 5-HT antagonist/reuptake inhibitor) has anticonvulsant and pro-convulsant effects. Materials and Methods: Electroconvulsions and four chemicals (pentylenetetrazole, 3-mercaptopropionic acid, thiosemicarbazide and bicuculline) were used to induce seizures in animal models. Effects of the acute treatment with TH on the anticonvulsant action of three common antiepileptic drugs against the maximal electroshock (MES) test in mice were investigated. Results: In the MES model, protection effects were observed for the chronic but not acute treatment with TH. In chemicals, induced seizures models, the acute treatment with TH did not show anticonvulsant and proconvulsant effects in 3-mercaptopropionic acid, thiosemicarbazide and bicuculline-induced seizure models. While it showed proconvulsant effects in the PTZ model, exacerbating the convulsion and death at a dose of 100 mg kg–1 singly administered. In the test to ascertain the effect of TH on the anti-MES action of three antiepileptics, the anticonvulsant effect of valproate was enhanced through the single administration of TH. While the anti-MES activity of carbamazepine and oxcarbazepine was weakened by acute TH when applied with a clinical dose or higher. Conclusion: The obtained results suggested that the TH has no anticonvulsant and proconvulsant effects under the clinic dosage but it can interfere with the anticonvulsive action of other antiepileptic drugs when combined.