OBJECTIVES: To assess the efficacy and tolerability of zonisamide in a study allowing flexible dosing in a more diverse and less refractory population than assessed in randomized controlled trials. METHODS: This 19-week, non-comparative study of adjunctive zonisamide included 281 adults who had at least four partial-onset seizures within 8 weeks on one or two antiepileptic drugs. Alterations to zonisamide doses were allowed after titration, except during two fixed-dose periods (weeks 10-13 and 16-19). RESULTS: At the end of the second fixed-dose period (median dose 300 mg/day), the median reduction in monthly seizure frequency was 33.3-41.1%; > or =50% responder rate was 40.9-44.2%; and seizure freedom rate was 15.0-15.9%, depending on the analysis used. The most common adverse events were fatigue (16.7%) and somnolence (15.3%). CONCLUSIONS: Zonisamide demonstrated efficacy in a setting more reflective of clinical practice and was generally well tolerated.