Background: mSCUC is an aggressive cancer with historically poor outcomes. Methods: We performed a retrospective analysis of 216 pts with mSCUC treated at MD Anderson from 1985-2020. We captured baseline demographic and clinical characteristics, metastatic sites, systemic treatments, and survival. Median overall survival (mOS) was calculated from start of frontline (1L) therapy for metastatic disease. Results: Median age was 67 years, 84% male sex, 91% primary tumor in bladder, and 88% white race. Histology included pure SCUC (30%), predominant SCUC (44%), focal SCUC (25%) and large cell (1%). Metastatic sites were lymph nodes (54%), bone/peritoneum (39%), liver (38%), brain (31%) and lung (26%). Brain metastases frequency varied across histology (pure SCUC 48%, predominant SCUC 24.5%, focal SCUC 24%, p=0.06). Treatment regimens and mOS by frontline regimen are listed (Table). mOS was 11.91 months for treated pts with sufficient follow up (n=155). mOS by 1L treatment: EP (9.51 months), IA/EP (14.10 months), other platinum chemotherapy (13.26 months), nonplatinum chemotherapy (9.74 months), immune checkpoint inhibitor (ICI) (6.51 months), EP+ICI (undefined). Of 140 pts treated with 1L chemotherapy, 43 (31%) were able to receive second line (2L) therapy. mOS among those who received 2L chemotherapy (n=27) was 13.65 months vs those who received 2L ICI (n=16) was 22.53 months (HR=0.53, 95% CI=0.26-1.10; p=0.11). Conclusions: mSCUC is a devastating malignancy with high degree of brain involvement, and poor prognosis. 1L ICI therapy alone has suboptimal survival outcomes and a chemotherapy backbone remains necessary. A deeper understanding of SCUC’s driver biology is essential for developing better therapies.