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The real-world survival outcomes and prognostic factors among patients receiving first-line targeted therapy for advanced renal cell carcinoma (aRCC) are not well known.Adult patients diagnosed with RCC and treated with first-line targeted therapy were identified from the Surveillance, Epidemiology, and End Results–Medicare database (January 1, 1993 to December 31, 2012). The patients were grouped into early (2006-2009) or late (2010-2012) targeted therapy era cohorts by the year of the first-line targeted therapy initiation. Overall survival (OS) was measured from first-line targeted therapy initiation and compared between the 2 cohorts using Kaplan-Meier analyses. The prognostic factors for OS were assessed using a multivariable-adjusted Cox model.A total of 604 and 641 aRCC patients (mean age, 68 years; ˜60% male in both cohorts) initiated first-line targeted therapy during the early and late targeted therapy eras, respectively. OS was significantly longer in the late than in the early targeted therapy era. Higher tumor grades (hazard ratio [HR], 1.61; 95% confidence interval [CI], 1.31-2.00) and lung (HR, 1.27; 95% CI, 1.06-1.53), bone (HR, 1.37; 95% CI, 1.13-1.66), and liver (HR, 1.42; 95% CI, 1.10-1.84) metastases were associated with significantly shorter OS. Previous nephrectomy (HR, 0.55; 95% CI, 0.42-0.72) and pazopanib as first-line targeted therapy relative to sorafenib (HR, 0.56; 95% CI, 0.37-0.85) or sunitinib (HR, 0.65; 95% CI, 0.44-0.95) were associated with significantly longer OS.The results of these real-world analyses suggest progress in aRCC management and identified positive (nephrectomy, pazopanib vs. sunitinib or sorafenib) and negative (higher tumor grade and lung, bone, or liver metastasis) prognostic factors among patients receiving first-line targeted therapy.Using the Surveillance, Epidemiology, and End Results–Medicare database, we assessed overall survival (OS) among renal cell carcinoma patients who had initiated first-line targeted therapy. OS was significantly longer in the late (2010-2012) versus early (2006-2009) targeted therapy era. Positive (nephrectomy, pazopanib vs. sunitinib or sorafenib) and negative (higher tumor grade and lung, bong, or liver metastases) OS prognostic factors were identified.