OBJECTIVE: Examine the possible association between long-term seizure outcome in childhood absence epilepsy (CAE) and the initial treatment choice. METHODS: Children with CAE were prospectively recruited at initial diagnosis and followed in a community-based cohort study. Children presenting with convulsive seizures, significant imaging abnormalities, or who were followed <5 years were excluded. Early outcomes included success of initial medication, early remission, and pharmacoresistance. The primary long-term outcome was complete remission: >/=5 years both seizure free and medication free. Survival methods were used for analyses. RESULTS: The first medication was ethosuximde (ESM) in 41 (69%) and valproic acid (VPA) in 18 (31%). Initial success rates were 59% (ESM) and 56% (VPA). Early remission and pharmacoresistance were similar in each group. Apart from atypical electroencephalography (EEG) features (61% [VPA], 17% [ESM]), no clinical features varied substantially between the treatment groups. Complete remission occurred in 31 children (76%) treated with ESM and 7 (39%) who received VPA (p = 0.007). Children with versus without atypical EEG features were less likely to enter complete remission (50% vs. 71%, p = 0.03). In a Cox regression, ESM was associated with a higher rate of complete remission than VPA (hazards ratio [HR] 2.5, 95% confidence interval [CI] 1.1-6.0; p = 0.03). Atypical EEG features did not independently predict outcome (p = 0.15). Five-year and 10-year remission, regardless of continued treatment, occurred more often in children initially treated with ESM versus VPA. SIGNIFICANCE: These findings are congruent with results of studies in genetic absence models in rats and provide preliminary evidence motivating a hypothesis regarding potential disease-modifying effects of ESM in CAE. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here.