PURPOSE: Targeted therapy and immunotherapy promise improved survival in patients with advanced melanoma, yet the effectiveness and cost-effectiveness of multigene panel sequencing compared with single-gene METHODS: Our population-based quasi-experimental retrospective target trial emulation used comprehensive patient-level data for 364 British Columbia, Canada, adults with an advanced melanoma diagnosis receiving multigene panel sequencing or single-gene RESULTS: We matched 147 multigene panel patients to controls, achieving balance for all covariates. After matching, ITT incremental costs were 9,447 CAD (95% CI, -8,516 to 6,006) and incremental LYG were 0.22 (95% CI, -0.05 to 0.49). We found uncertainty in differences on OS using Kaplan-Meier ( CONCLUSION: The cost-effectiveness of multigene panels was evenly poised at higher thresholds, even when accounting for treatment initiation. Health systems reimbursing multigene panels and expensive therapies may be confronted with a value tradeoff, in which there may be improved survival albeit with a modest change in cost-effectiveness.