Background: The anti-angiogenic tyrosine kinase inhibitor (TKI) anlotinib has been approved for the treatment of advanced clear cell sarcoma, alveolar soft-part sarcoma, and other anthracycline-failed advanced soft tissue sarcoma (STS) in China. However, the management of refractory STS is still an unmet medical need. The formation of immunosuppressive microenvironment is one of the resistance mechanisms of anti-angiogenic therapy. This retrospectively observational study investigated the efficacy and safety of anlotinib rechallenge combined with immune checkpoint inhibitor (ICI) for advanced STS after progression on anlotinib treatment. Methods: A cohort of STS patients who had progressed after the anlotinib treatment were prescribed with anlotinib plus ICI were enrolled. Other concurrent systemic treatments were not allowed. Demographic features and clinical outcomes were reviewed and analyzed. Results: A total of 10 STS patients were included. The median of previous systemic treatment regimens was 3 (range, 1-5). Two cases (20%) were observed a partial response, including anlotinib plus nivolumab for a leiomyosarcoma and anlotinib plus toripalimab for an angiosarcoma. Another 4 patients achieved stable disease lasting more than 6 weeks. The median progression-free survival (PFS) were 4.8 months (95% CI: NA-12.5 months). Three (30%) patients developed grade 3 or higher adverse events including toxicity of skin/mucosal(n = 2) and neutrophile granulocyte decreased(n = 1). Conclusions: ICIs plus anlotinib rechallenges maybe a potential treatment for advanced STS patients after progression on anlotinib with acceptable adverse events.