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Lenvatinib plus pembrolizumab or everolimus have considerable clinical benefits. However, it is controversial whether the high-cost combination regimen will be approved by the guidelines and widely used in clinical practice. Based on current prices, lenvatinib plus pembrolizumab is a cost-effective treatment option. Our conclusions provide objective data reference for clinicians when making clinical decisions, individual treatment of patients, and reference for national health insurance decision-making. Introduction: The CLEAR trial indicated that survival benefits were generated with lenvatinib plus pembrolizumab (LP) or everolimus (LE) than with sunitinib for advanced renal cell carcinoma (aRCC). However, the high cost of immuno-target and dual-targeted treatment, we assessed the costeffectiveness of lenvatinib plus pembrolizumab or everolimus in the first-line setting for treatment of patients with aRCC from the United States (US) payers' perspective. Materials and Methods: A comprehensive Markov model was developed to evaluate the cost and effectiveness of LP or LE in first-line therapy for aRCC. We estimated life years (LYs), quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios (ICERs). Utility values and direct costs related to the treatments were gathered from the published studies. Then, one-way and probabilistic sensitivity analyses were performed. Additional subgroup analyses were considered. Results: Treatment with LP and LE provided an additional 0.67 QALYs (0.62 LYs) and 0.66 QALYs (0.90 LYs) compared with sunitinib, resulting in ICER of $131,656 per QALY and 201,928 per QALY, respectively. The most influential factor in this model was the cost of pembrolizumab with LP. Probabilistic sensitivity analysis showed there was a 58.97% and 28.91% probability that LP and LE were cost-effective at WTP values of $150,000 per QALY in the US. Subgroup analyses demonstrated that LP was more cost-effective for patients from Western Europe and North America, intermediate risk of the International risk group of Metastatic Renal Cell Carcinoma Database Consortium (IMDC), favorable and intermediate risk group of Memorial Sloan Kettering Cancer Center (MSKCC) and PD-L1 combined positive score greater than or equal to 1%. Conclusion: From the perspective of the US payer, LP is a cost-effective option as first-line treatment for patients with aRCC at a WTP threshold of $150,000 per QALY, but LE is the opposite. [ABSTRACT FROM AUTHOR]