OBJECTIVES:  Estimate the overall cost and health outcomes associated with commonly used treatment sequences in patients with metastatic renal cell carcinoma in the United States. METHODS:  A patient-level simulation using discretely integrated condition event modeling method was developed to estimate the survival and costs accrued on treatment sequences. The model assessed sequences that started with either pazopanib or sunitinib, which are commonly used first-line agents, followed by nivolumab, cabozantinib, axitinib, everolimus, or lenvatinib+everolimus as second-line agents. Patients received best subsequent care after the second line of treatment, with the assumption that it did not impact estimated survival. Efficacy data for pazopanib and sunitinib were obtained from published literature. For nivolumab and everolimus, underlying risk equations for disease progression, treatment discontinuation, and survival were developed using patient-level data from the CheckMate 025 trial. The equations accounted for the baseline patient characteristics (Memorial Sloan Kettering Cancer Center score) and key predictive clinical events, such as response achievement and duration of response, with each individual treatments. Efficacy of cabozantinib, axitinib, and lenvatinib+everolimus was incorporated based on a network meta-analysis. Adverse event rates were obtained from published literature for all therapies. Treatment, administration, adverse event management, and monitoring costs were obtained from published literature and publicly available sources. RESULTS:  The model-estimated cost/life-years gained were $314,914/4.2 years for nivolumab, $324,251/4.0 years for cabozantinib, $264,776/3.2 years for axitinib, $270,726/2.8 years for everolimus, and $684,626/5.1 years for lenvatinib+everolimus–containing sequences. The model suggested that treatment sequences with nivolumab as the second-line therapy had the lowest cost per life-year gained ($74,589/life-year) versus treatment algorithms with other targeted agents as second-line therapy (range, $81,378–$134,496/life-years). CONCLUSIONS:  Treatment sequences that utilize sequential therapy with sunitinib or pazopanib followed by nivolumab may offer improved life expectancy at a lower cost versus the sequences that utilize second-line agents other than nivolumab.