OBJECTIVES:  Lacosamide was recently approved as monotherapy for adults with focal seizures in the European Union (already approved in USA). Comparative data are needed to inform clinical decision-making. This network meta-analysis (NMA) compared lacosamide with other antiepileptic drugs (AEDs). METHODS:  Randomized, controlled trials of AED monotherapy in newly-diagnosed patients (aged ≥16 years) were identified via systematic literature review. NMA was performed to obtain relative estimates for efficacy (6 and 12-month seizure-freedom) and safety (discontinuations due to adverse events [AEs], serious treatment-emergent-AEs [TEAEs], serious drug-related-AEs [DRAEs]) for the overall population and elderly subpopulation. Efficacy analyses used pooled data for immediate-release and controlled-release (CR) carbamazepine. RESULTS:  Data from twelve trials evaluating ten AEDs were analyzed. For 6-month seizure-freedom, lacosamide showed similar efficacy to carbamazepine (odds ratio [OR]: 1.23 [95% Credible Interval: 0.91-1.63]) and levetiracetam (1.25 [0.77-1.91]), with numerically better efficacy versus other AEDs (lamotrigine: 1.39 [0.62-2.70]; zonisamide: 1.63 [0.99-2.52], phenytoin: 1.92 [0.66-4.46]). Comparison with valproate showed large uncertainty (0.70 [0.08-2.59]). Lacosamide showed similar efficacy to carbamazepine for 12-month seizure-freedom (1.02 [0.77-1.32]), with OR versus other AEDs ranging from 1.18 (levetiracetam) to 1.66 (lamotrigine). Lacosamide tended towards numerical advantages versus levetiracetam, carbamazepine-CR, and zonisamide for discontinuations due to AEs (OR range: 0.48-0.74) and for risk of serious TEAEs versus carbamazepine-CR and zonisamide (range: 0.78-0.90). Risk of serious DRAEs for lacosamide (0.38 [0.10-0.90]) and levetiracetam (0.33 [0.06-0.95]) was similar versus carbamazepine-CR. Similarly, elderly subpopulation analyses showed similarities between lacosamide, lamotrigine, and levetiracetam when compared to each other and versus carbamazepine-CR (with some numerical advantages) on seizure-freedom, and serious DRAEs. CONCLUSIONS:  Numerical benefits versus other AEDs indicate lacosamide is a valuable addition to the armamentarium of focal seizure monotherapies. However, the available evidence was insufficient to demonstrate meaningful differences between AEDs for efficacy outcomes, as reflected by the wide Credible Intervals. STUDY SUPPORT: UCB Pharma-sponsored.