Background: Renal medullary carcinoma (RMC) is one of the most lethal renal cell malignancies with a median overall survival (OS) of only 13 months from diagnosis (Shah et al. BJU Int., 2017). RMC predominantly affects young individuals of African descent and is characterized by loss of the tumor suppressor SMARCB1 in all cases. Platinum-based chemotherapy produces a best response rate of 29% and is the recommended front line therapy for RMC (Msaouel et al. Clin Genitourin Cancer, 2019). However, there is little data on subsequent therapies. We recently showed that loss of SMARCB1 induces replication stress that renders RMC cells vulnerable to nucleoside analogs such as gemcitabine (Gem) and topoisomerase inhibitors such as doxorubicin (Dox) (Msaouel et al. Cancer Cell, 2020). We therefore hypothesized that Gem + Dox would demonstrate clinical activity against RMC. Methods: We conducted a retrospective study of patients who were treated with Gem + Dox for metastatic RMC at our institution. A blinded board-certified radiologist reviewed all restaging images to assess best radiographic response as defined by RECIST v1.1 and, when applicable, date of progression. Adverse events (AEs) were evaluated using the CTCAE version 5.0 grading estimated from chart documentation. Results: Between 01/2005 and 09/2020, we identified 16 patients with RMC that were treated with Gem + Dox and were evaluable for survival outcomes (Table). All but 1 patient (94%) had received prior platinum-based chemotherapy. Gem + Dox produced a partial response in 3/14 evaluable patients (21.4%) and stable disease as best response in 10/14 (71.4%), resulting in a median progression-free survival of 3.0 months (mo) with 95% CI 1.5-4.5 mo. The median overall survival (OS) from the start of Gem + Dox was 9.8 mo (95% CI 3.3-16.2) and the median OS from diagnosis was 18.6 mo (95% CI 11.3-25.9). Gem + Dox was well tolerated with no grade ≥ 4 AEs and the most common grade 2 or 3 AE’s were cytopenias (3/17), nausea (3/17), and fatigue (2/17). There were no grade ≥ 2 reported events of cardiotoxicity, but 3 patients discontinued treatment due to reaching recommended maximum dose of Dox. Conclusions: Gem + Dox demonstrated clinical benefit in patients with RMC and was well tolerated in most patients, supporting its use in patients with RMC whose disease progressed on prior platinum-based chemotherapy. Further investigation is warranted to determine and target mechanisms of resistance.