Background Valproate is widely accepted as a drug of fi rst choice for patients with generalised onset seizures, and its broad spectrum of effi cacy means it is recommended for patients with seizures that are diffi cult to classify. Lamotrigine and topiramate are also thought to possess broad spectrum activity. The SANAD study aimed to compare the longer-term eff ects of these drugs in patients with generalised onset seizures or seizures that are diffi cult to classify. Methods SANAD was an unblinded randomised controlled trial in hospital-based outpatient clinics in the UK. Arm B of the study recruited 716 patients for whom valproate was considered to be standard treatment. Patients were randomly assigned to valproate, lamotrigine, or topiramate between Jan 12, 1999, and Aug 31, 2004, and follow-up data were obtained up to Jan 13, 2006. Primary outcomes were time to treatment failure, and time to 1-year remission, and analysis was by both intention to treat and per protocol. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN38354748. Findings For time to treatment failure, valproate was signifi cantly better than topiramate (hazard ratio 1·57 [95% CI 1·19–2·08]), but there was no signifi cant diff erence between valproate and lamotrigine (1·25 [0·94–1·68]). For patients with an idiopathic generalised epilepsy, valproate was signifi cantly better than both lamotrigine (1·55 [1·07–2·24] and topiramate (1·89 [1·32–2·70]). For time to 12-month remission valproate was signifi cantly better than lamotrigine overall (0·76 [0·62–0·94]), and for the subgroup with an idiopathic generalised epilepsy 0·68 (0·53–0·89). But there was no signifi cant diff erence between valproate and topiramate in either the analysis overall or for the subgroup with an idiopathic generalised epilepsy. Interpretation Valproate is better tolerated than topiramate and more effi cacious than lamotrigine, and should remain the drug of fi rst choice for many patients with generalised and unclassifi ed epilepsies. However, because of known potential adverse eff ects of valproate during pregnancy, the benefi ts for seizure control in women of childbearing years should be considered.