Background: C-reactive protein (CRP) has been demonstrated to be an independent predictor of survival outcomes in renal cell carcinoma (RCC). The use of biomarkers to predict post-surgical complications is not well studied. We sought to investigate predictive factors for major complications following surgery for RCC and delineate their impact on mortality outcomes. Methods: We performed a two-center retrospective analysis of patients who underwent partial (PN) and radical nephrectomy (RN) for RCC. Patients who had complications within 30 days after surgery were identified and the complications were scored using the Clavien-Dindo classification system. Patients were grouped based on whether they experienced 30-day major (Clavien ≥3) complications and whether they had elevated preoperative CRP defined as >5mg/L. Primary outcome was non-cancer mortality (NCM), with secondary outcomes being all-cause (ACM) and cancer-specific (CSM) mortality. Multivariable analyses (MVA) were conducted to evaluate predictors for Clavien ≥3 complications, NCM, CSM, and ACM. Kaplan-Meier analyses (KMA) were performed to compare overall survival (OS), noncancer-specific survival (NCS), and cancer-specific survival (CSS) between patients with non-elevated and elevated preoperative CRP and between patients without and with 30-day Clavien ≥3 complications. Results: A total of 2,234 patients were analyzed [116 (5.2%) experienced Clavien ≥3 complications; median follow up 44 months]. MVA revealed that coronary artery disease (OR 2.37, p=0.005), elevated CRP (OR 2.25, p=0.004), PN (OR 2.79, p<0.001), and open surgical approach (OR 1.74, p=0.049) were predictive of Clavien ≥3 complications. Additionally, MVA demonstrated that elevated CRP was an independent predictor of NCM (HR 2.50, p=0.009), CSM (HR 5.51, p<0.001) and ACM (HR 4.04, p<0.001), while presence of 30-day Clavien ≥3 complications was independently associated with worsened NCM (HR 3.05, p=0.042) but not CSM or ACM. KMA comparing non-elevated and elevated preoperative CRP revealed significant differences for 5-year OS (96.0% vs. 66.8%, p<0.001), 5-year CSS (98.2% vs. 75.6%, p<0.001), and 5-year NCS (97.6% vs. 87.7%, p<0.001). KMA comparing patients without and with 30-day Clavien ≥3 complications revealed significant differences for 5-year OS (87.3% vs. 80.7%, p=0.015) and 5-year NCS (95.6% vs. 87.0%, p<0.001), but not 5-year CSS (91.3% vs. 88.9%, p=0.601). Conclusions: In patients undergoing surgical resection for RCC, elevated preoperative CRP was an independent risk factor for development of 30-day Clavien ≥3 complications, while elevated CRP and development of Clavien ≥3 complications were associated with worsened NCM. Our findings suggest an interplay between major complications and NCM in patients who undergo surgery for RCC, with elevated preoperative CRP being a predictor for both.