Background: Clinical management of metastatic melanoma (MM) after PD-1 blockade failure remains a challenge and lacks a standard of care. Chemo-immunotherapy (CIT) combinations have demonstrated favorable efficacy and safety profiles in lung cancer patients (pts). Our pre-clinical study has shown that in MM pts who have failed PD-1 blockade, the addition of chemotherapy can reshape a subset of tumor-reactive CD8+ T cells, resulting in enhanced anti-tumor immune responses. We conducted a retrospective study comparing the clinical outcomes of CIT with immunotherapy or chemotherapy alone after PD-1 blockade failure. Methods: We retrospectively reviewed MM pts seen at Mayo Clinic, Rochester between Jan, 2012 and Jun, 2017 who had failed anti-PD1 therapy. We identified 48 pts who received subsequent CIT (carboplatin/paclitaxel n = 22; temazolomide n = 1, nab-paclitaxel n = 1), or immune checkpoint inhibitors (ICI) or chemotherapy alone. The overall survival (OS), objective response rate (ORR), time-to-next therapy (TTNT), and toxicities were assessed between these groups. Results: Among the 48 pts, 24 received CIT after disease progression on PD-1 blockade. At median follow up of 3.9 years, pts who received CIT had a median OS of 5 years (95% CI: 2-NR) versus 1.8 years (95% CI: 0.9-2; p = 0.002) for those who received either ICI (n = 9) or chemotherapy alone (n = 15), with ORR of 61% versus 17% (p = 0.001), respectively. The median TTNT was 8 months (95% CI: 6-15) for CIT cohort versus 3.4 months (95% CI: 2.8-4; p = 0.004) for those who received ICI or chemotherapy alone. Conclusions: In MM pts who have failed anti-PD-1 therapy, the chemo-immunotherapy combination showed favorable clinical outcomes and acceptable toxicity profile. This regimen should be considered for MM pts in this setting who have limited treatment options.