Objective To evaluate the efficacy, tolerability, and safety of once‐daily 1200 mg and 2400 mg SPN‐804 (Oxtellar XR™, Supernus Pharmaceuticals), an extended‐release tablet formulation of oxcarbazepine (OXC), added to 1‐3 concomitant antiepileptic drugs (AEDs) in adults with refractory partial‐onset seizures, with or without secondary generalization. Methods The Prospective, Randomized Study of OXC XR in Subjects with Partial Epilepsy Refractory (PROSPER) study was a multinational, randomized, double‐blind, parallel‐group Phase 3 study. The primary efficacy endpoint was median percent reduction from baseline in monthly (28‐day) seizure frequency for the 16‐week double‐blind treatment period in the intent‐to‐treat (ITT) population with analyzable seizure data. Other efficacy analyses included proportion of patients with ≥ 50% seizure reduction, proportion of patients seizure free, and the relationship between clinical response and plasma concentration. Results Median percent reduction was ‐28.7% for placebo, −38.2% (P = 0.08 vs placebo) for once‐daily SPN‐804 1200 mg, and −42.9% (P = 0.003) for SPN‐804 2400 mg. Responder rates were 28.1%, 36.1% (P = 0.08), and 40.7% (P = 0.02); 16‐week seizure‐free rates in a pragmatic ITT analysis were 3.3%, 4.9% (P = 0.59), and 11.4% (P = 0.008), respectively. When data were analyzed separately for study site clusters, a post hoc analysis demonstrated that both SPN‐804 dosages were significantly superior to placebo in median percent seizure reduction (placebo: −13.3%; 1200 mg: −34.5%, P = 0.02; 2400 mg: −52.7%, P = 0.006) in the North American study site cluster. A concentration–response analysis also supported a clinically meaningful effect for 1200 mg. Adverse event types reflected the drug's established profile. Adverse event frequency was consistent with a pharmacokinetic profile in which SPN‐804 produces lower peak plasma concentrations vs immediate‐release OXC. Once‐daily dosing was not associated with any new safety signals. Conclusions Adjunctive once‐daily SPN‐804 improved seizure control in patients with inadequately controlled partial‐onset seizures. Adverse event occurrence and discontinuations due to adverse events suggest improved tolerability vs previously published data with immediate‐release OXC.