Background: SCC is an uncommon variant of bladder cancer with sparse data pertaining to its genomic landscape. Utilizing Tempus Lens, a real world clinical and genomic dataset, we investigated the clinical and genomic characteristics of SCC compared to UC. Methods: The de-identified Tempus Lens dataset was queried for patients diagnosed with UC or SCC of the bladder or ureter, of any stage. Baseline demographic, pathologic features, and results from blood or tissue-based genomic sequencing were catalogued. Clinical and pathological variables were summarized using descriptive statistics to compare the UC and SCC groups, using a Chi-square or Fisher’s exact test for a significance threshold of P<0.05. The prevalence of genomic alterations in the two groups were compared using a two proportions Z-test with a significance level of 0.00167, calculated using the Bonferroni correction for multiple comparisons. Results: A total of 4,569 pts (UC: 4429; SCC: 140) were included in the analysis. Gender, race, the proportion of patients ≥65 years, stage, and tumor grade were similar between the two groups. Use of blood based genomic sequencing was relatively similar (29.8% and 27.1%) between UC and SCC patients, respectively. Compared to UC, the SCC cohort had a significantly higher prevalence of TP53 (93.6% vs 60.8%; P<0.001), RB1 (73.6% vs 21.5%; P<0.001), and PTEN (13.6% vs 5.1%; P<0.001) alterations, and a lower frequency of CDKN2A (7.1% vs 29.5%; P<0.001), MTAP (2.9% vs 18%; P <0.001) and FGFR3 (6.4% vs 15.6%; P=0.003) mutations. Actionable alterations in SCC cohort included PIK3CA (21.4%), ERBB2 (13.6%), ATR (13.6%), ATM (9.3%), BRCA2 (8.6%), MSH6 (5.7%), TSC1/2 (4.9%), and PMS2 (4.3%). Conclusions: This is the largest study characterizing the genomic features of SCC. Our findings are consistent with prior studies suggesting a distinct genomic profile of SCC, with actionable alterations in a significant subset of patients. The impact of these alterations on outcomes and therapeutic strategies targeting these mutations warrant further investigation.