Background: Sarcomas are a type of cancer that have been historically difficult to treat given their rarity, numerous subtypes, and variable response to treatment. Doxorubicin is the most used first-line chemotherapy in metastatic sarcoma; pegylated liposomal doxorubicin (PLD) has been explored as a potentially better tolerated alternative to free doxorubicin, with less myelosuppression, alopecia, and potentially less cardiotoxicity. In this work, we examine the efficacy and real-world challenges of using PLD as treatment for metastatic and locally advanced sarcoma. Methods: Medical records of metastatic and locally advanced sarcoma patients treated with single agent PDL as a therapy were obtained from a single tertiary medical center. Retrospective analysis was conducted to measure overall survival, progression free survival, best overall RECIST response, dosage, and complications. Results: 58 subjects were identified with 52% being male and 48% female. Sarcoma subtypes included liposarcoma (28%), leiomyosarcoma (21%), undifferentiated sarcoma (16%), synovial sarcoma (5%), and other subtypes (30%). Mean age at time of initiating therapy was 64 years. 22% of patients had previously been treated with doxorubicin, in the neo-adjuvant or adjuvant setting. Patients received an average of 5 cycles of PLD. Starting dosage was 50 mg/m² every 28 days, however, changes to lower the starting dose were made in 38% of cases to adjust for anticipated tolerance, and in 21% subsequently due to side effects such as cutaneous toxicity and fatigue. There were no complete responses, 12% partial response, 31% stable disease, and 57% progressive disease. Mean overall survival and progression free survival was 452 and 180 days, respectively. Sixty-seven percent of participants had at least one follow-up echocardiogram, and 15% of those had some evidence of cardiotoxicity, with an ejection fraction of < 50% or 10% decrease from baseline. Of the participants with changes in ejection fraction, 67% had received prior anthracycline therapy and 33% had received a total lifetime dose of doxorubicin exceeding the recommended 500 mg/m² limit. Conclusions: PLD is an option for first-line therapy for metastatic sarcoma in general, however, its efficacy remains limited in a real-world setting with most patients showing a best RECIST response of progressive disease and a mean progression free survival of 180 days. While PLD is generally well-tolerated, there are potential toxicities that require attention, including cutaneous toxicity, such as hand-foot syndrome, and infusion reactions. Furthermore, a significant portion of our sample had echocardiographic changes, with decreased ejection fraction, pointing out that, while PLD may be less cardiotoxic than free doxorubicin, there is potential risk. This highlights the need to continue the search for novel therapeutic strategies in metastatic and locally advanced sarcoma.