Soft tissue sarcomas constitute a heterogeneous group of tumors of mesenchymal origin: at present, more than 50 separate histological subtypes of soft tissue sarcoma have been listed. Although there have been advances in the understanding of these tumors and their treatment over the past few years, there is still a lack of consensus on the standard of care, and new therapeutic options are eagerly awaited. Trabectedin has been approved for the treatment of patients with advanced soft tissue sarcomas after failure of anthracyclines and ifosfamide. However, the effectiveness and tolerability of this agent in retroperitoneal soft tissue sarcomas have been poorly characterized. Here we report the cases of two monorenal patients with a retroperitoneal sarcoma who achieved prolonged stabilization of disease with trabectedin. Trabectedin-associated toxicities were generally mild and were successfully managed by supportive care. Of note, the patients did not experience clinically relevant myelosuppression, which is currently considered the limiting toxicity of trabectedin.