Background: The renin-angiotensin system (RAS), traditionally associated with blood pressure regulation and fluid balance, also plays a role in tumor development and growth among several cancer types. Renin-angiotensin system inhibitors (RASI), such as angiotensin converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARBs), have been shown in studies of various malignant neoplasms to be associated with improved outcomes. In metastatic urothelial cancer, the use of ACEI and ARBs has been associated with higher rates of tumor regression among patients (pts) receiving immunotherapy (IO) with PD1/L1 inhibitors. One potential mechanistic explanation is RASI-induced downregulation of TGF-beta, for which high expression is a known mechanism of PD1/L1 inhibitor resistance. While the development of novel IO therapies has changed the treatment landscape for mRCC, only one study to date has examined the impact of RAS inhibition in pts with mRCC receiving IO. We hypothesized that concurrent RASI in pts with mRCC receiving IO is associated with increased tumor regression. Methods: We conducted a retrospective analysis of pts with mRCC receiving immunotherapy as a first or second line of treatment from 2016-2023 at the University of Virginia. A logistic regression model was used to evaluate the impact of concurrent RASI on tumor regression. The primary endpoint in this study was any regression of tumor on imaging. Results: Data were available for 147 pts with mRCC who received IO as a first- (n=104, 70.7%) or second- (n=43, 29.3%) line treatment. 52 pts (35.4%) received ACEI/ARBs during IO; 42 pts (40.4%) who received IO as first-line treatment were on ACEI/ARBs and 10 patients (23.2%) who received IO as a second-line treatment were on ACEI/ARBs. Analysis showed that pts who received ACEI or ARBs during IO were more likely to have tumor regression compared to pts who were not on concurrent RASI (OR 7.43 [95% CI 2.70-23.53], p=0.0002). This held true regardless if pts received IO as a first-line (OR 6.02 [95% CI 1.84-23.38], p=0.005) or second-line (OR 9.71 [95% CI 1.51-122], p=0.032) treatment. Conclusions: Our hypothesis generating study suggests that in our RCC population the concurrent use of RASI in pts with mRCC receiving IO was associated with a significantly increased likelihood of tumor regression. These findings highlight the potential therapeutic advantage of RASI in combination with IO for mRCC pts. Further exploration of this association is warranted in prospective studies to improve treatment outcomes for this patient population.