Purpose: This multicenter study, to our knowledge, is the first phase III trial to compare trabectedin versus dacarbazine in patients with advanced liposarcoma or leiomyosarcoma after prior therapy with an anthracycline and at least one additional systemic regimen. Patients and Methods: Patients were randomly assigned in a 2:1 ratio to receive trabectedin or dacarbazine intravenously every 3 weeks. The primary end point was overall survival (OS), secondary end points were disease control-progression-free survival (PFS), time to progression, objective response rate, and duration of response-as well as safety and patient-reported symptom scoring. Results: A total of 518 patients were enrolled and randomly assigned to either trabectedin (n = 345) or dacarbazine (n= 173). In the final analysis of PFS, trabectedin administration resulted in a 45% reduction in the risk of disease progression or death compared with dacarbazine (median PFS for trabectedin v dacarbazine, 4.2 v 1.5months; hazard ratio, 0.55; P<.001); benefitswere observed across all preplanned subgroup analyses. The interim analysis of OS (64%censored) demonstrated a 13%reduction in risk of death in the trabectedin arm compared with dacarbazine (median OS for trabectedin v dacarbazine, 12.4 v 12.9months; hazard ratio, 0.87; P5.37). The safety profileswere consistent with thewell-characterized toxicities of both agents, and the most common grade 3 to 4 adverse effects were myelosuppression and transient elevation of transaminases in the trabectedin arm. Conclusion: Trabectedin demonstrates superior disease control versus conventional dacarbazine in patients who have advanced liposarcoma and leiomyosarcoma after they experience failure of prior chemotherapy. Because disease control in advanced sarcomas is a clinically relevant end point, this study supports the activity of trabectedin for patients with these malignancies.