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Objective: Existing gene panels were developed to understand the etiology of epilepsy, and further benefits will arise from an effective pharmacogenomics panel for personalizing therapy and achieving seizure control. Our study assessed the cost-effectiveness of a pharmacogenomics panel for patients with drug-resistant epilepsy, compared with usual care., Methods: A cost-utility analysis was employed using a discrete event simulation model. The microsimulation model aggregated the costs and benefits of genetically guided treatment versus usual care for 5000 simulated patients. The 10-year model combined data from various sources including genomic databases on prevalence of variants, population-level pharmaceutical claims on antiseizure medications, published long-term therapy retention rates, patient-level cost data, and systematic reviews. Incremental cost per quality-adjusted life-year (QALY) gained was computed. Deterministic and probabilistic sensitivity analyses were undertaken to address uncertainty in model parameters., Results: The mean cost of the genetically guided treatment option was AU$98 199 compared with AU$95 386 for usual care. Corresponding mean QALYs were 4.67 compared with 4.28 for genetically guided and usual care strategies, respectively. The incremental cost per QALY gained was AU$7381. In probabilistic sensitivity analyses, the incremental cost per QALY gained was AU$6321 (95% uncertainty interval = AU$3604-AU$9621), with a 100% likelihood of being cost-effective in the Australian health care system. The most influential drivers of the findings were the monthly health care costs associated with reduced seizures, costs when seizures continued, and the quality-of-life estimates under genetically guided and usual care strategies., Significance: This early economic evaluation of a pharmacogenomics panel to guide treatment for drug-resistant epilepsy could potentially be cost-effective in the Australian health care system. Clinical trial evidence is necessary to confirm these findings., (© 2022 International League Against Epilepsy.)