Tuberous sclerosis complex (TSC) is an autosomal dominant syndrome with a variable neurocognitive phenotype. Recently, different intelligence profiles were observed for distinct mutation types and locations, suggesting that individuals with missense mutations represent a subgroup with milder neurocognitive outcomes. We applied these recent insights to the analysis of the epilepsy phenotype in a large cohort of patients with TSC. Associations between genotype and a history of epilepsy and/or infantile spasms (IS) were explored retrospectively, using data from 478 TSC patients from the databases of the Tuberous Sclerosis Alliance and the Herscot Center at Massachusetts General Hospital. Absolute and relative risks for IS and other types of epilepsy were calculated for various mutation classes, selected according to type and location. As expected, TSC2 mutations were associated with a significantly higher occurrence of IS and other epilepsy types. However, missense mutations located in the central region of TSC2 (exons 23-33) were associated with a significantly reduced incidence of IS. Our study further delineates the epilepsy phenotype in TSC patients. Identifying distinct epilepsy phenotypes for specific mutation subgroups may help identify relevant biomarkers and assist clinicians in making treatment decisions. © 2012 Elsevier B.V.