Dacarbazine is an important drug in the therapeutic landscape of leiomyosarcoma (LMS). Alkylating agents are subjected to resistance mechanisms based on anti-apoptotic pathways and repair mechanisms, including the DNA repair enzyme O6-methylguanine-DNA methyltransferase (MGMT). In this retrospective study, the methylation status of theMGMTpromoter in histological tumor samples from patients with LMS, dacarbazine-based regimens-treated, was measured and correlated with clinical outcomes aimed at optimizing the use of dacarbazine in soft tissue sarcomas. The patients with unmethylatedMGMThad better outcomes than those with methylatedMGMT. Patients withoutMGMTmethylation had better Progression Free Survival (PFS) when aged ≥62 years compared to those aged <62 years, while PFS of patients with methylatedMGMTwas less favorable independently of age (p= 0.0054). The patients without a methylatedMGMTgene had higher Disease control rate (DCR). These results are not in agreement with the role of the methylatedMGMTgene in other tumors, and with this study, we demonstrated the correlation between methylatedMGMTand poor prognosis; despite that, sample smallness, heterogeneity of LMS and of treatment history could be selection bias. Predictive markers of response to chemotherapies in sarcomas remain an unmet need.