Non-lymphoid mesenchymal neoplasms of salivary gland origin are rare, accounting for 1.9–5% of major salivary gland tumors. We describe the clinico-pathologic features of 18 cases of mesenchymal neoplasms of the major salivary glands experienced at Asan Medical Center, Seoul, Korea, from 1998 to 2004. Mesenchymal neoplasms accounted for 3.4% of the total of 524 major salivary gland tumors. The parotid gland was the preponderant site (15 cases). Thirteen tumors were benign, constituting 3.5% of the total of 371 benign neoplasms. Schwannomas were the most common benign tumors (six cases), followed by lipomas (three cases), plexiform neurofibroma, hemangioma, desmoid tumor, and solitary fibrous tumor (one each). The malignant tumors consisted of one dermatofibrosarcoma protuberans, synovial sarcoma, leiomyosarcoma, pleomorphic liposarcoma and desmoplastic small round cell tumor each. Immunohistochemical analysis for the expresssion of vimentin, actin, desmin, neuron-specific enolase, keratin, CD34, CD99 and bcl-2 contributed to the differential diagnoses. Genetic analysis for fusion transcripts was conclusive in the diagnosis of desmoplastic small round cell tumor, which is extremely rare at this location. Pre-operative imaging study and fine needle aspiration cytology had limitations in prediction of the mesenchymal nature of the tumors, due to either low index of suspicion, similarities to mixed tumors, or specimen inadequacy. Awareness of the development of various mesenchymal tumors in the major salivary glands could increase the accuracy of preoperative and postoperative diagnosis, and therapeutic efficacy.