Trabectedin is a novel antineoplastic agent approved as monotherapy in patients with advanced soft tissue sarcoma (STS) after failure of standard therapy with anthracyclines or ifosfamide, or patients who are unsuited to receive these agents. Some histotypes of STSs appear to be particularly sensitive to trabectedin, but the sensitivity of some rare STSs histological subtypes to the drug is rather unknown. We report on two patients suffering from infrequent subtypes of STSs, fibrosarcoma and epithelioid sarcoma, who were treated with trabectedin. In these cases the treatment completely failed, and right after the first cycle of trabectedin administration an unusually rapid tumor growth and dissemination was documented. Of note, one of the patients showed objective response to MVIP chemotherapy (methotrexate, etoposide, ifosfamide and cisplatin), after trabectedin failure. Trabectedin activity against several subtypes has not been studied or well-documented due to the rarity and numerous histotypes of STSs. Case studies aiming at the individualization of treatment options against specific STS subtypes will further justify the usage of this agent in clinical practice.