A key therapeutic goal of metastatic renal cell carcinoma (mRCC) treatment is delayed disease progression. The degree to which early therapeutic success affects downstream outcomes is not well established. To assess the clinical and economic impact of early vs delayed disease progression in patients with mRCC treated with first-line (1L) tyrosine kinase inhibitors (TKIs) followed by second-line (2L) therapy in the US Veterans Health Administration (VHA) database. Adult patients newly diagnosed with mRCC who were treated with a TKI as 1L therapy and who progressed to 2L therapy from October 1, 2013, through March 31, 2018, were identified from the US VHA database. Patients were stratified by median time from initiation of 1L therapy to initiation of 2L therapy into early (median time or sooner)and delayed (longer than the median) progression cohorts. Clinical outcomes (time to 2L therapy discontinuation, time to third-line [3L] treatment initiation, and overall survival) were assessed descriptively, and health care resource utilization and costs were compared between patients in the early and those in the delayed progression cohorts. Survival analyses (Kaplan-Meier curves) were used to estimate descriptively the median time to discontinuation, time to next line of treatment, and time to death for each cohort. Multivariate analysis was performed to adjust for the influence of differences in cohort characteristics, and Cox proportional hazards models were used to descriptively assess the impact of predictive factors on clinical outcomes. 289 patients were included in the analysis: 145 in the early progression cohort and 144 in the delayed progression cohort. Baseline characteristics were similar between the early and delayed progression cohorts. Median time from 1L therapy initiation to 2L therapy discontinuation was 7.9 months in the early progression cohort and 18.0 months in the delayed progression cohort, whereas time from 1L therapy initiation to 3L therapy initiation was 9.4 and 21.8 months, respectively; overall survival was 19.7 and 36.4 months, respectively. Descriptive analysis revealed generally lower risks for 2L therapy discontinuation (HR = 0.40, 95% CI = 0.31-0.52), 3L therapy initiation (HR = 0.42, 95% CI = 0.32-0.55), and death (HR = 0.46, 95% CI = 0.33-0.64) for those with delayed progression. After adjustment for possible confounding factors, comparative analysis during the follow-up period showed that delayed progression was associated with a shorter median all-cause hospital length of stay (0.4 days vs 0.8 days for early progression; = 0.0004), fewer pharmacy visits (3.57 vs 4.08 visits; = 0.0266), and lower total health care costs ($10,342 vs $13,388; = 0.0347) per patient per month. In patients with mRCC, early progression after 1L therapy initiation is associated with generally worse clinical outcomes and statistically significantly greater health care resource utilization and costs than delayed progression. This finding highlights the importance of initiating therapy with an optimal 1L treatment regimen that has been proven to delay disease progression. This study was sponsored by EMD Serono Inc., an affiliate of Merck KGaA, and Pfizer Inc. EMD Serono Inc. and Pfizer Inc. were involved in the study design; the collection, analysis, and interpretation of the data; the writing of the report; and the decision to submit the report for publication. Liu and Bhanegaonkar are employed by EMD Serono Inc., an affiliate of Merck KGaA. Kasturi was employed by EMD Serono Inc., an affiliate of Merck KGaA, at the time of this study. Kim and Krulewicz are employed by Pfizer Inc. Dieyi is an employee of STATinMED Research, which received consulting fees from EMD Serono Inc. and Pfizer Inc. Hutson has received grants from Pfizer Inc., Astellas Pharma Inc., Janssen Pharmaceuticals, Exelixis, Inc., and Eisai Co., Ltd., outside of this work. Data from this analysis were presented at the Virtual International Society for Pharmacoeconomics and Outcomes Research 2020 conference, May 18-20, 2020; the virtual American Society of Clinical Oncology Annual Meeting, May 29-31, 2020; and AMCP Nexus 2020 Virtual, October 20-23, 2020.