Spindle cell lipoma (SCL) and pleomorphic lipoma constitute a spectrum of lipomatous lesions with distinctive clinicopathological features. Multiple variants of SCL have been reported including fibrous, plexiform, vascular, pseudoangiomatous, low-fat/fat-free, and myxoid changes. This paper describes an unusual patient with a 1-cm submucosal nodular lesion excised from the buccal mucosa of a 55-year-old woman with classic histopathological and immunohistochemical features of "low-fat" plexiform SCL with prominent myxoid stroma, which initially suggested a soft-tissue myxomatous lesion other than SCL. The current lesion exhibited microscopically few adipocytes supported by network-like myxoid proliferations with retraction artifacts from the surrounding stromal connective tissue. Immunohistochemistry was positive for vimentin, CD34, CD10, and S100, the latter only on adipocytes. The Ki-67 was <1%. Pan-cytokeratin (AE1/AE3), desmin, alpha-SMA, EMA, bcl-2, p53, and remarkably retinoblastoma protein (pRb) were negative. "Low-fat" plexiform SCL bear no significant prognostic significance, but this lesion may challenge the diagnosis even experienced pathologists.