Introduction: Seizure is a dysfunction of the brain. The drugs that are more effective in the treatment of seizures and have the least complications are considered as favorable. In this study, we compared the effect of levetiracetam with valproate sodium as an add-on therapy in controlling seizures in patients with epilepsy. Methodology: In this study, 200 patients aged 14 to 75 years suffering from refractory epilepsy, either partial or generalized types, were included. Half of the patients received valproate sodium and the other half received levetiracetam as the add-on therapy for lamotrigine. For the levetiracetam group, a six-week period was considered for the drug to reach appropriate blood levels and in the next six weeks, the patients were examined for clinical and EEG symptoms, liver enzymes and CBC, and the results were compared with the conditions before treatment. Results: The add-on therapy with valproate and levetiracetam, both decrease the frequency and duration of seizures. The side effects of levetiracetam were found to be conventional complications (such as dizziness, insomnia and somnolence), which are often transient. However, valproate had additional side effects such as hypersensitivity, hair loss, tremor and weight gain. Also, the results of laboratory tests during the study indicated changes in liver enzyme of four cases in the valproate group whereas there were not any notable enzyme changes in levetiracetam group. Conclusion: This study showed that levetiracetam and valproate were both effective in alleviating epilepsy, resistant to monotherapy with lamotrigine, and reduced the frequency and time of seizures and improved the lives of individuals as well.