Background: High rates of disease control with systemic therapy (ST) in the post-cytokine era for metastatic renal cell carcinoma (mRCC) cause apprehension that cytoreductive nephrectomy (CN) may delay effective therapy. We therefore evaluated factors associated with early mortality and time to ST after CN. We hypothesized markers of poor performance status and morbid CN would be associated with postoperative mortality and therapeutic delays. Methods: The National Cancer Database was screened for adult mRCC cases having CN followed by ST, years 2006-2013. We classified a delay in systemic therapy as interval > 45 days (median time to ST in the cohort). Multivariable logistic regression was performed, identifying factors associated with perioperative mortality and delays to initiation of ST. Results: Of 10,913 patients with initial CN (45% of mRCC), 30- and 90-day mortality were 3% and 11%, respectively. 6,362 later received ST (87% targeted therapy, 13% immunotherapy), median start was 45 days post-operatively (IQR 9-72), with 73% receiving ST within 30 days of CN. Multivariable factors associated with 30-day mortality included, older age, (OR 2.3, 95% CI 1.5-3.5 for those >75 [referent < 55 years]), Charlson index >0 (OR 1.3, 95% CI 1.0-1.6), lack of insurance (OR 1.9, 95% CI 1.2-2.8 [referent private payer]), node-positive disease (OR 1.4 95% CI 1.1-1.7), length of stay > 90^th percentile (> 10 days, OR 3.2, 95% CI 2.0-5.3), larger tumor size (T4 lesion OR 1.7, 95% CI 1.2-2.5 [referent T1]). Delayed ST was associated with travel burden > 50 miles (OR 1.2, 95% CI 1.0-1.4), concurrent metastasectomy (OR 1.3, 95% CI 1.2-1.5), and length of stay > 90^th percentile (OR 1.5, 95% CI 1.1-2.3). Conclusions: These data suggest that markers of frailty, more progressive disease, and surgical morbidity may contribute to surgical-related deaths or hinder patients receiving potentially disease-controlling therapy when treated with initial CN in mRCC. Going forward, existing surgical prognostic models could incorporate risks of surgical-related mortality and delay to ST when considering CN.