AbstractObjectiveEpilepsy with generalized tonic–clonic seizures alone (GTCA) is a common but poorly characterized idiopathic generalized epilepsy (IGE) syndrome. Hence, we investigated electroclinical features, seizure outcome, and antiseizure medication (ASM) withdrawal in a large cohort of GTCA patients.MethodsIn this multicenter retrospective study, GTCA patients defined according to the diagnostic criteria of the International League Against Epilepsy (2022) were included. We investigated prognostic patterns, drug resistance at the last visit, and ASM withdrawal, along with their prognostic factors.ResultsWe included 247 patients with a median (interquartile range [IQR]) age at onset of 17 years (13–22) and a median follow‐up duration of 10 years (IQR = 5–20). Drug resistance at the last visit was observed in 40 (16.3%) patients, whereas the median latency to achieve 2‐year remission was 24 months (IQR = 24–46.5) with a median number of 1 (IQR = 1–2) ASM. During the long‐term follow‐up (i.e., 202 patients followed ≥5‐years after the first ASM trial), 69 (34.3%) patients displayed an early remission pattern and 36 (17.9%) patients displayed a late remission pattern, whereas 16 (8%) and 73 (36.3%) individuals had no‐remission and relapsing–remitting patterns, respectively. Catamenial seizures and morning predominance of generalized tonic–clonic seizures (GTCS) independently predicted drug resistance at the last visit according to multivariable logistic regression. Treatment withdrawal was attempted in 63 (25.5%) patients, with 59 (93.7%) of them having at least a 12‐month follow‐up after ASM discontinuation. At the last visit, 49 (83%) of those patients had experienced GTCS recurrence. A longer duration of seizure freedom was the only factor predicting a higher chance of successful ASM withdrawal according to multivariable Cox regression.SignificanceGTCA could be considered a relatively easily manageable IGE syndrome, with a low rate of drug resistance and a high prevalence of early response to treatment. Nevertheless, a considerable proportion of patients experience relapsing patterns of seizure control, highlighting the need for appropriate counseling and lifestyle recommendations.