Objective: Generic substitution of antiepileptic drugs (AEDs) may be problematic in patients receiving multiple generics because variability in drug serum concentrations can induce breakthrough seizures. To investigate clinical consequences of generic substitution of one versus multiple generics of topiramate (Topamax®). Methods: Claims data of Régie de l'assurance-maladie du Québec (RAMQ) from January 2006-October 2007 were used. Patients with epilepsy (ICD-9 345 or 780.3) treated with topiramate (Canadian patent expired January 2006) were selected. An open-cohort person-time design was used to classify the observation period into mutually exclusive periods of brand, single-generic, and multiple-generic use. One-year switching rates of brand-to-generic and switchback-to-brand were computed using Kaplan-Meier methodology. Medical resource utilization (frequency per person–year) was compared among the three periods using multivariate regressions adjusted for demographics, treatment characteristics and comorbidities. Results: A total of 948 patients were observed during 1105 person-years (p/y) of brand use, 233 p/y of single-generic use, and 92 p/y of multiple-generic use. Approximately 38% of brand users switched to generic topiramate, of whom 14% switched back to brand. Generic users received on average 1.4 generic versions, with 23% taking two or more versions. Multiple-generic use was associated with increased utilization of both AEDs and non-AED drugs compared to brand (RR=1.27, 95%CI=1.24; 1.31) and single-generic use (RR=1.10, 95%CI=1.06; 1.13) after covariate adjustment. Multiple-generic use was associated with significantly higher hospitalization rate (0.48 vs. 0.83 visit/p/y, RR=1.65, 95%CI=1.28; 2.13) and hospital length of stay (2.6 vs. 3.9 days/p/y, RR=1.43, 95%CI=1.27; 1.60), but the effect was less pronounced in single-generic use (hospitalization: RR=1.08, 95%CI=0.88; 1.34, length of stay: RR=1.12, 95%CI=1.03; 1.23). The risk of head injury or fracture was 5 times higher (HR=5.43, 95%CI=4.23; 6.97) following a generic-to-generic switch compared to brand use. Conclusion: Multiple-generic substitution of topiramate was significantly associated with outcomes, such as hospitalizations, fractures and injuries.