Background: This subgroup analysis of a phase 3 study compares outcomes for eribulin versus dacarbazine in patients with leiomyosarcoma. Methods: Patients ≥18 years old with advanced liposarcoma or leiomyosarcoma, ECOG PS ≤2, and ≥2 prior treatment regimens were randomly assigned (1:1) to eribulin mesylate (1.4 mg/m² intravenously on day 1 and day 8) or dacarbazine (either 850, 1000, or 1200 mg/m² intravenously) every 21 days until disease progression. The primary end point was OS; additional end points were progression-free survival (PFS) and objective response rate (ORR). Results: 309 Patients with leiomyosarcoma were included (eribulin, n = 157; dacarbazine, n = 152). Median age was 57 years; 42% of patients had uterine disease and 57% had nonuterine disease. Median OS was 12.7 versus 13.0 months for eribulin versus dacarbazine, respectively (hazard ratio [HR] = 0.93 [95% CI 0.71–1.20]; P = 0.57). Median PFS (2.2 vs 2.6 months, HR = 1.07 [95% CI 0.84–1.38]; P = 0.58) and ORR (5% vs 7%) were similar between eribulin- and dacarbazine-treated patients. Grade ≥3 TEAEs occurred in 69% of patients receiving eribulin and 59% of patients receiving dacarbazine. Conclusions: Efficacy of eribulin in patients with leiomyosarcoma was comparable to that of dacarbazine. Both agents had manageable safety profiles.