OBJECTIVES Epilepsy heavily affects the quality of life (QoL) of patients with brain tumor because in addition to taking treatments for the oncological illness, patients are required to live with the long-term taking of antiepileptic drugs (AEDs). The AEDs' adverse effects are common in these patients and can negatively influence their perceptions of their QoL.We conducted an observational pilot study in patients with brain tumor-related epilepsy to verify efficacy, tolerability, and impact on QoL and global neurocognitive performances of zonisamide (ZNS) in add-on. MATERIALS AND METHODS We recruited 13 patients (5 females, 8 males; mean age, 49.6 years) presenting uncontrolled seizures. At first visit and at final follow-up at 6 months, patients underwent neurological examination, evaluation of adverse events, and cognitive and QoL tests. A seizure diary was given. RESULTS Eight patients underwent chemotherapy, 3 underwent radiotherapy, and 5 had disease progression. Mean dosage of ZNS at final follow-up was 300 mg/d.Of 9 patients who reached the sixth month follow-up, the mean weekly seizure number before ZNS had been 3.2 ± 5.0, and at final follow-up, the mean weekly seizure number was 0.18 ± 0.41 (P = 0.05).Compared with baseline, we observed stability in all cognitive domains, except for verbal fluency that significantly worsened.Results on QoL tests showed that QoL remained unchanged over time, which could indicate that ZNS did not influence the patients' perceived QoL. CONCLUSIONS Zonisamide as add-on in our patients seems to be well tolerated and efficacious in controlling seizures. Despite having limitations represented by the fact that our study is observational, with a small study population and a short follow-up period, our results confirm that when choosing an AED, in addition to efficacy, the drug's effect on patients' QoL also needs to be considered, especially for patients facing many psychosocial challenges, such as those with brain tumor-related epilepsy.