An international trial comparing remacemide hydrochloride with carbamazepine was undertaken in individuals with newly diagnosed epilepsy using a novel double-blind, parallel-group, double triangular sequential design. Patients with two or more partial or generalized tonic–clonic seizures in the previous year were randomized to remacemide or carbamazepine and titrated to a target dose of 600mg/day. Subsequent dosage adjustments were allowed while maintaining the blind. Repeated assessments of neuropsychological function and mood were carried out using computerized and conventional measures. The trial was completed 20 months after initiation, following the second interim analysis. Efficacy as measured by seizure recurrence showed remacemide to be inferior to carbamazepine. Baseline cognitive and neuropsychological measures showed impairment across the whole patient population. Cognitive/neuropsychological performance at 8, 24, and 48 weeks was compared with that at baseline. Significant deterioration was seen on measures of information processing speed and attention after treatment with carbamazepine. The study data provide evidence for the utility and sensitivity of a number of cognitive assessments, which may be employed in future trials of antiepileptic drugs.