Purpose: To compare the safety and efficacy of first-line chemotherapy regimen with or without doxorubicin intreating patients with advanced soft tissue sarcoma (STS). Patients and Methods: We retrospectively analyzed acohort of 56 patients histologically confirmed with STS who were treated at Jiangsu Cancer Hospital and ResearchInstitute from July 2011 to June 2012.The basic element of first line chemotherapy contained epirubicin in groupB and lacked epirubicin in group A. Response was assessed using RECIST criteria. The Kaplan-Meier methodwas used to estimate progress free survival (PFS). Results: According to RECIST criteria , patients in grouptreated by chemotherapy without epirubicin, the objective response (OR) ratio was 6.5 % (CR0%+PR6.5%).Disease control rate (DCR=CR+PR+SD) was 25.8% with a median follow-up of 14.6 months, including 2 patientsachieving a partial response (PR 6.5%) and a stable response (SD 19.4%) in 6. In group B with epirubicin basedregimens, no patient had complete response, PR (28 %) was observed in 7 and SD (24 %) in 6. DCR was observedin 13 patients (52%). By Fisher’s exact test, the DCR difference between the two groups was statistically significant(p=0.046). In group A, median PFS was 3.0 months (95%CI:2.1-3.8), compared with 4.0 months (95% CI:3.03-4.97) in group B (p=0.0397 by log-rank test). Epirubicin based chemotherapy and ECOG performance status 0-1were identified as favorable factors for progression in our cohort of patients. Differences of nonhematologic andhematologic toxicities were not statistically significant between the two groups, and the addition of epirobicinwas not associated with cardiac toxicity (p=0.446). Conclusion: Our study demonstrates that epirubicin-basedchemotherapy is effective and well tolerated, and is superior to chemotherapy without epirubicin regardingefficacy. Therefore it is recommended that epirubicin-based chemotherapy should be considered as first line forpatients with advanced STS.