Background: Receipt of adjuvant therapy has become a standard of care for management of high risk localized renal cell carcinoma (RCC), with emerging literature demonstrating longer disease-free survival. Neoadjuvant approaches have been utilized investigationally to facilitate complete surgical resections in high risk and complex renal masses. We sought to evaluate outcomes of patients treated with neoadjuvant or adjuvant therapy in non-metastatic RCC utilizing a propensity score model. Methods: We queried the INMARC database for patients with localized surgically treated RCC who underwent systemic neoadjuvant or adjuvant therapy. Neoadjuvant therapy was defined as presurgical therapy given in the setting of localized disease and adjuvant therapy as systemic therapy given postoperatively in the absence of documented metastases. Patients with metastases at time of diagnosis were excluded from the analysis. A propensity score match (PSM) model in a 1:3 ratio was conducted within a caliper width of 0.1 including: age, sex, hypertension, Charlson Comorbidity Index, tumor size, tumor necrosis, stage, surgical margin, tumor grade and type of surgery [radical vs. partial nephrectomy]. Primary outcome was all-cause mortality (ACM), and secondary outcome was cancer-specific mortality (CSM). Multivariable analysis (MVA) via Cox regression was fitted for the outcomes of interest. Kaplan-Meier analysis (KMA) for overall (OS), cancer specific survival (CSS) was conducted for 5-year survival assessment. Results: After PSM 293 patients were analyzed [adjuvant n=203, (69.2%), 109 targeted therapy (TT) vs. 94 immunotherapy; neoadjuvant n=90, (30.7%), 59 TT vs. 31 immunotherapy]; median follow up was 50 (IQR 20-76) months from surgery . MVA revealed adjuvant vs. neoadjuvant (HR 1.98, p=0.007) and positive margin (HR 2.01, p=0.046) to be associated with increased risk of ACM; immunotherapy vs. TT (HR 0.47, p=0.001) was associated with a decreased risk. MVA for CSM revealed that adjuvant vs. neoadjuvant (HR 2.18, p=0.016) and positive margin (HR 2.41, p=0.028) were associated with increased risk of CSM, while immunotherapy vs. TT (HR 0.35, p<0.001) was associated with decreased risk. KMA comparing neoadjuvant vs. adjuvant 5-year OS was 80.4% vs. 64.8% (p=0.04), while CSS was 88.1% vs. 76.2% (p=0.03). Conclusions: In a comparison of patients with localized RCC who underwent adjuvant or neoadjuvant systemic therapy, receipt of neoadjuvant therapy was associated with superior survival outcomes. These findings are hypothesis generating and call for consideration for a clinical trial to compare outcomes of adjuvant vs. neoadjuvant therapy in high-risk localized RCC.