<h3>BACKGROUND CONTEXT</h3> The effectiveness of starting systemic therapies after surgery for spinal metastases from renal cell carcinoma (RCC) has not been evaluated in randomized clinical trials. Agents that target tyrosine kinases, mammalian target of rapamycin signaling, and immune checkpoints are now commonly used. Variables like sarcopenia, nutritional status, and frailty may impact recovery from spine surgery and are considered when evaluating a patient's candidacy for such treatments. Better understanding the significance of these variables may help improve patient selection for available treatment options after surgery. <h3>PURPOSE</h3> Study the treatment effect of postoperative systemic therapies on survival. <h3>STUDY DESIGN/SETTING</h3> Observational study using comparative effectiveness methods. <h3>PATIENT SAMPLE</h3> Adult patients who underwent spine surgery for metastatic renal cell carcinoma (RCC) between 2010-2019 at Massachusetts General Hospital. <h3>OUTCOME MEASURES</h3> The primary outcome of this study is overall survival. <h3>Methods</h3> Univariable and multivariable Cox regression analyses were performed to determine factors associated with overall survival (OS) in a retrospective cohort of adult patients who underwent spine surgery for metastatic RCC between 2010-2019. Propensity score matched (PSM) analysis and inversive probability weighting (IPW) were performed to determine the treatment effect of postoperative systemic therapy on OS. To address confounding and minimize bias in estimations, PSM and IPW were adjusted for covariates including age, gender, frailty, sarcopenia, nutrition, visceral metastases, IMDC (International Metastatic RCC Database Consortium) risk score, and performance status. <h3>Results</h3> Eighty-eight patients (73.9% male; median age, 62 [29-84] years) were identified. Forty-nine of 88 (55.7%) had intermediate IMDC risk and 29 of 88 (33.0%) had poor IMDC risk. Median follow-up was 17 months (1-104 months) during which 57 (64.7%) died. Poor IMDC risk (HR, 3.2, [1.08-9.3]), baseline performance status (ECOG 3-4; HR, 2.7 [1.5-4.7]), and nutrition (prognostic nutritional index 1st tertile; PNI <40.74; HR=2.69, [1.42-5.1]) were associated with worse OS. Sarcopenia and frailty were not significantly associated with poor survival. Postoperative systemic therapy was associated with prolonged OS, demonstrated by similar effects from multivariable Cox analysis (HR, 0.55 [0.30-1.00]), PSM (HR, 0.53 [0.29-0.93]), and IPW (HR, 0.47 [0.24-0.94]) and comparable confidence intervals. Median survival for those receiving postoperative systemic therapy was 28 (CI 95%, 19-43) months versus 12 (CI 95%, 4-37) months for those who only had surgery (log-rank P = .027). <h3>Conclusions</h3> This comparative analysis demonstrates that postoperative systemic therapy is associated with improved survival in specific cohorts with metastatic spinal RCC after adjusting for frailty, sarcopenia, and malnutrition. The marked differences in survival should be taken into consideration when planning for surgery. <h3>FDA DEVICE/DRUG STATUS</h3> This abstract does not discuss or include any applicable devices or drugs.