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Myxofibrosarcoma is one of the most common types of soft tissue sarcomas occurring in the lower limbs of male older adults. Mainstay treatment is surgical intervention with chemoradiotherapy with a combination of doxorubicin and ifosfamide with brachytherapy if advanced or metastatic. There are no guidelines on the combination of immunotherapy with radiation therapy for myxofibrosarcoma. We report the first documented case of unresectable multifocal myxofibrosarcoma that was treated with pembrolizumab and radiation therapy for first-line therapy with a significant response. We also highlight genomic markers and immune radiation priming therapy, forecasting favorable response in treatment with pembrolizumab.