Background: Pembrolizumab/axitinib significantly prolonged progression-free survival (PFS) and overall survival (OS) vs. sunitinib in a phase 3 trial KEYNOTE-426 among previously untreated patients with advanced renal cell carcinoma (RCC). This study assessed the cost-effectiveness of pembrolizumab/axitinib vs. other first-line treatments of advanced RCC from a US payer perspective. Methods: A partitioned survival model with 3 states (progression-free, progressed, death) evaluated costs and quality-adjusted life years (QALYs) for pembrolizumab/axitinib and other first-line regimens: sunitinib and pazopanib in the overall population; sunitinib, cabozantinib, and nivolumab/ipilimumab in the subgroup with poor/intermediate IMDC risk. Time on treatment, PFS, and OS were extrapolated using parametric models fitted to KEYNOTE-426 data (24 Aug 2018 cutoff) for pembrolizumab/axitinib and sunitinib, and hazard ratios from network meta-analyses for other comparators. Costs of first-line and subsequent treatment, adverse events, medical resources, and terminal care were estimated based on trial results, drug labels, and published sources. Utilities were derived through mixed-effects regressions of KEYNOTE-426 EQ-5D data. Results: Over a lifetime, the incremental cost-effectiveness ratios (ICERs) for pembrolizumab/axitinib were below willingness-to-pay thresholds of $150,000/QALY or $180,000/QALY (approx. 3 × gross domestic product per capita) vs. all comparators in the overall and intermediate/poor risk populations (table). Results were robust in deterministic and probabilistic sensitivity analyses. Conclusions: Pembrolizumab/axitinib is associated with higher QALYs and considered cost-effective vs. other first-line treatments of advanced RCC in the US.