Background: Trials of salvage therapy for advanced UC have required prior platinum-based therapy. This practice requires scrutiny since non-platinum-based first-line therapy may be offered to cisplatin-ineligible patients (pts). We examined the impact of prior exposure to first-line platinum vs. non-platinum based chemotherapy on overall survival (OS) with salvage systemic chemotherapy. Methods: Data of pts receiving salvage systemic chemotherapy were collected retrospectively or from trials. Data on prior first-line platinum exposure were required in addition to the known prognostic factors: treatment free interval, hemoglobin, performance status, albumin and liver metastasis status. Cox proportional hazards regression was used to evaluate their association with OS after accounting for salvage therapy with single agent chemotherapy or combination chemotherapy. Results: Data was obtained from 455 pts exposed to prior platinum and 37 pts not exposed to prior platinum. In the group exposed to prior platinum, salvage therapy consisted of a single agent taxane (n = 184) and taxane containing combination chemotherapy (n = 271). In the group not exposed to prior platinum, salvage therapy consisted of single agent taxane or vinflunine (n = 20), single agent 5-fluorouracil (n = 1), taxane containing combination chemotherapy (n = 12), carboplatin-based combinations (n = 2) and cisplatin-based combinations (n = 2). The median OS for the prior platinum group was 7.8 (95% CI: 7.0, 8.1) months (mo), and for the prior non-platinum group was 9.0 (6.0, 11.0) mo (p = 0.50). In a multivariable analysis including major prognostic factors and after controlling for single agent or combination salvage chemotherapy, prior platinum vs. no prior platinum exposure conferred no independent impact on OS (HR 1.10 [0.75, 1.64], p = 0.62). Conclusions: Prior platinum vs. non-platinum based chemotherapy did not confer a prognostic impact on OS after accounting for major prognostic factors in pts receiving salvage systemic chemotherapy for advanced UC. Lack of exposure to prior platinum should not disqualify pts from inclusion in trials of salvage therapy after accounting for the 5 known prognostic factors.