BACKGROUND AND OBJECTIVES: More than half of people undergoing epilepsy surgery become seizure-free and may consider withdrawing antiseizure medications (ASMs). Withdrawal practices vary, and the optimal timing remains unclear. We aim to compare seizure relapse risk among individuals initiating ASM withdrawal at different time points after epilepsy surgery. METHODS: We conducted a multicenter observational cohort study of adults who underwent resective epilepsy surgery between 1990 and 2016 at 12 tertiary centers. Participants were seizure-free before medication withdrawal and had at least 1 year of follow-up. Seizure relapse risk was compared among those initiating withdrawal 1, 2, 3, 4, or 5 years postoperatively vs later. We used propensity score matching for each comparison to adjust for treatment selection bias. RESULTS: Of the 964 people included (51% female; median age at surgery 34 years [interquartile range 26-44]), 446 (46%) began ASM withdrawal in the first year after surgery, 255 (26%) in the second, 110 (11%) in the third, 58 (6%) in the fourth, 29 (3%) in the fifth, and 66 (7%) after the fifth year. After matching, those starting withdrawal in the first (hazard ratio [HR] 1.4; p = 0.003) or second (HR 1.18; p < 0.001) year had a higher risk of relapse than those who withdrew later. Starting withdrawal in the third (HR 1.7; p = 0.12), fourth (HR 1.3; p = 0.45), or fifth (HR 0.17; p = 0.82) year after surgery showed no increase in risk compared with later withdrawal. Long-term outcomes, such as seizure freedom and being entirely off ASMs at the final follow-up, were not substantially associated with withdrawal timing. DISCUSSION: Initiating ASM withdrawal within the first 2 postoperative years was linked to a higher initial risk of seizure relapse compared with later withdrawal, although long-term outcomes were similar regardless of withdrawal timing. Waiting more than 2 years did not confer additional benefit in reducing seizure risk. Deciding whether and when to withdraw ASMs is a shared process involving individuals, caregivers, and clinicians, balancing preferences, risk of injury, social factors (e.g., driving, work, and supervision), and clinical judgment. Transparent information on risks and benefits is essential. Our findings offer real-world evidence that may inform future evidence-based withdrawal protocols and follow-up strategies.