OBJECTIVE To examine the influence of side of pathology and gender on changes in cognitive function across the adult lifespan in a homogenous sample of patients with mesial temporal lobe epilepsy (MTLE) associated with unilateral hippocampal sclerosis (HS). METHODS We retrospectively examined the neuropsychological profiles of 382 patients in 3 cohorts: cohort 1 aged 18-30 (n = 171), cohort 2 aged 31-45 (n = 170), and cohort 3 aged 46-65 (n = 41). All participants had medically intractable seizures associated with unilateral HS and an onset of epilepsy in childhood, with an average onset at 7 years. RESULTS There were no significant differences between the age cohorts on the measures of intellect, language, or memory. Duration of epilepsy (years) was not related to IQ, memory, or language scores in any group. Male subjects performed better than female subjects on verbal IQ, performance IQ, and naming tasks. Verbal learning and recall scores were worse in those with left than right HS. CONCLUSIONS Our findings suggest that the profile of cognitive deficits associated with MTLE is already established as children with temporal lobe epilepsy enter adulthood. While memory and language skills are maximally affected, intellectual function is also compromised in MTLE. This profile appears to remain stable across the adult lifespan, at least until 60 years of age, despite the intractable nature of the seizures. Side of pathology and gender are significant mediating factors in shaping the profile of cognitive deficits associated with childhood-onset MTLE, with people with left-sided HS and female subjects particularly vulnerable to more widespread cognitive dysfunction.