Background: Cigarette smoking is a known risk factor for the development of renal cell carcinoma (RCC), and active smoking has been associated with decreased survival in patients (pts) receiving systemic targeted therapies for RCC. The impact of smoking status on tumor genomics in other malignancies has been evaluated, particularly in urothelial carcinoma. Here, we investigated the impact of smoking status on genomic alterations and outcomes in pts with RCC. Methods: Pts with history of RCC who underwent genomic sequencing between 2015-2023 at Indiana University were included. Baseline demographic and disease characteristics were summarized. Pts were classified by smoking history into either no smoking history or history of smoking, which included both pts who currently or previously smoked. Comparisons between groups were done using the Chi-square test for categorical variables and Wilcoxon test for continuous variables. Kaplan-Meier method was used to analyze progression free survival (PFS) and overall survival (OS), using the log rank test to compare groups. Results: 144 pts were included. 63 (43.8%) were never smokers, 58 (40.3%) previously smoked, and 23 (16.0%) currently smoked. 103 (71.5%) were male. Median age at diagnosis was 58yrs (range: 24-83). Pts who currently smoked had a median age of 52 yrs vs. 59yrs for both pts who previously smoked and who never smoked (p=0.021). 133 pts (92.4%) were white. Histology was 69.4% clear cell, 9.0% unclassified, 9.1% papillary, 2.1% translocation, 2.1% collecting duct, 1.4% renal medullary, 1.4% chromophobe, 1.4% poorly differentiated, 0.7% mixed, and 3.4% other. Histology did not differ based on smoking status. Rhabdoid and/or sarcomatoid features were present in 28.8% of pts. 138 pts (95.8%) had metastatic disease. 65 pts (47.1%) presented with de novo metastatic disease. Metastasis sites included lung 56.9%, regional lymph nodes (LN) 40.3%, bone 31.9%, liver 17.4%, distant LN 18.8%, and brain 6.9%. The table lists genomic alterations in patients with and without a smoking history. Overall, 2-yr PFS was 9.2% and 2-yr OS was 86.5%. 2-yr PFS in pts with a smoking history was 9.2% vs. 8.6% in pts without a smoking history. 2-yr OS in pts with a smoking history was 90.1% vs. 82.3% in pts without a smoking history (p=0.49). Conclusions: In this cohort of pts, there was a trend toward more frequent PBRM1 mutations, which have been associated with improved response to immunotherapy, in pts with a history of smoking. Larger datasets are needed to further evaluate potential genomic differences based on smoking history that may reflect increased sensitivity to particular systemic therapies.