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Background: Evidence‐based recommendations for antiepileptic drug selection in cats beyond phenobarbital are limited, and additional studies are needed for cats where seizures remain inadequately controlled by administration of phenobarbital alone or for cats that cannot safely receive phenobarbital. Objective: To compare seizure frequency in cats before and after oral administration of zonisamide and describe adverse clinical or clinicopathologic effects in this cohort. Animals: Fifty‐seven cats with a history of seizures. Methods: Multicenter, retrospective study. Median number of seizures per month and number of seizure days per month were compared before and after administration of zonisamide in all cats, a subgroup of cats with idiopathic epilepsy (IE), and a subgroup of cats receiving zonisamide as sole therapy. Clinical and clinicopathologic adverse effect data were also reported. Results: A median decrease of 1 (P =.001, 95% confidence interval (CI) [−1.0, −0.5]) seizure per month, and 1 (P =.003, 95% CI [−1.5, −0.2]) seizure days per month was found across all cats after oral administration of zonisamide. The subgroup with IE showed median decreases of 1 (P =.03, 95% CI [−2.0, −0.5]) and 2 (P =.01, 95% CI [−2.5, −1.0]), respectively. The most common clinical adverse effects were sedation (17%), ataxia (11%), hyporexia (17%), and emesis (5%). One cat developed mild nonregenerative anemia, 2 cats developed mild metabolic acidosis, and 6 cats showed mild increases in ALT and ALP. Conclusion: Zonisamide was well tolerated and efficacious in controlling seizure activity in most cats. [ABSTRACT FROM AUTHOR]