This prospective, multicenter, non-interventional surveillance study (ZADE study) explored seizure outcome and tolerability of adjunctive treatment with zonisamide (ZNS) in a non-selected sample of patients with partial-onset seizures in everyday clinical practice. Changes in quality of life (QOL) and health status were also recorded. Clinical status was assessed before and 4 months after introduction of ZNS. The herein reported evaluation of QOL and health status was based on a representative subsample of 207 patients. In this subgroup, a reduced QOL had been apparent in 68% of patients at baseline. After introduction of ZNS, all measures improved, with ameliorations in QOL in up to 35% of patients. Major determinants for a better QOL outcome were (1) a better score at baseline, (2) a higher degree of seizure reduction, and (3) a lower number of concomitant AEDs. Tolerability was subjectively rated as good by 89% of patients. With a ZNS dose of 244.8 ± 108 mg/d at study end, seizure frequency had dropped from 8.8±19.2 within 8 weeks before baseline to 3.6 ± 9.1 seizures within the period of 8 weeks before study end. A total of 79% of patients responded to ZNS treatment with a ≥ 50% reduction in seizure frequency; 34% became seizure free. In conclusion, adjunctive treatment with ZNS seems to be efficacious and well tolerated. QOL improvement was predicted by baseline score, seizure outcome, and overall drug load, and is thus more likely a result of enhanced seizure control, rather than an intrinsic psychotropic effect of zonisamide.