Background: Both the microtubule-dynamics inhibitor eribulin and the multi-targeted tyrosine kinase inhibitor anlotinib exhibit single-agent anti-tumor activity in previously treated soft tissue sarcoma (STS). This study aimed to evaluate the efficacy and safety of the combination treatment of eribulin and anlotinib in patients with advanced STS. Methods: In this multi-center phase II study (ERAS), patients with advanced soft tissue sarcoma who relapsed/progressed after anthracycline chemotherapy or were not candidates for such treatment were included. Patients received eribulin (1.1 mg/m² intravenously on days 1 and 8) and anlotinib (12mg orally once daily on days 1-14) every 21 days for 6-8 cycles, followed by anlotinib maintenance. The primary endpoint was progression-free survival rate at 24 weeks (PFR_24w). Secondary endpoints included median progression-free survival (mPFS), median overall survival (mOS), objective response rate (ORR), disease control rate (DCR) and safety. Results: Thirty-one patients were enrolled. Twenty-eight (90.3%) patients had received anthracycline chemotherapy, and the remaining 3 (9.7%) were chemotherapy-naïve. Pathological types included L-type sarcomas (10 leiomyosarcomas and 6 dedifferentiated liposarcomas) and non-L-type sarcomas (n =15, with 8 subtypes). As of the cut-off date of Jan 28, 2024, the median follow-up time was 30.4 weeks. Response evaluation was feasible in 29 patients. The ORR, DCR and predicted PFR_24w were 20.7%, 82.8% and 65.5%, respectively. The mPFS was 30.1 weeks, with no significant difference observed between patients with L-type sarcomas and non-L-type sarcomas. The mOS was not reached. Nineteen (61.3%) patients experienced at least one grade 3/4 adverse event. The most common grade 3/4 adverse events included neutropenia (35.5%), leukopenia (25.8%), hypertension (16.1%), hypertriglyceridemia (16.1%) and increased gamma-glutamyl transpeptidase (16.1%). Conclusions: The combination of eribulin and anlotinib shows promising efficacy with an acceptable toxicity profile in patients with advanced STS, irrespective of pathological type. Clinical trial information: ChiCTR2300067650.