This report describes a spontaneous prostate fibromyxoid sarcoma with smooth muscle differentiation in an approximately 136-week-old intact male F344xBNF1 rat on a diet study for 2 weeks. At necropsy, the prostate was markedly distorted and enlarged by a firm white multinodular mass (6.0 × 4.5 × 3.5 cm). Histopathologically, the mass consisted of solid sheets of interlacing mesenchymal spindle cells with indistinct cell borders. Nuclei were separated by variable amounts of hyaline to fibrillar eosinophilic and/or myxomatous material. The extracellular myxomatous material tended to form whorls and stained positively with alcian blue. The mass stained strongly with Masson trichrome and vimentin throughout. Approximately 5% of the neoplastic cells were positive for smooth muscle actin, and none stained for desmin and pancytokeratin. To the authors' knowledge, this fibromyxoid sarcoma with smooth muscle differentiation is the first such described prostatic sarcoma in a rat.