Chondroid syringoma is an uncommon epithelial and mesenchymal neoplasm of eccrine sweat glands. Most are benign, but some may exhibit aggressive behavior, including local recurrence and lymph node or distant metastases. Treatment is generally limited to radical surgical excision and possibly chemoradiation, although the latter is generally considered ineffective against these tumors. Histologic features of benign and malignant chondroid syringoma are similar, thus making morphology an unreliable marker for clinically aggressive behavior. Identification of biomarkers that predict clinical behavior would be potentially useful for selecting patients with malignant chondroid syringoma for targeted therapy. The purpose of this study was to investigate somatic mutations commonly involved in tumor pathways, and to determine if there is altered expression of tumor suppressors p16 and p53 in metastatic malignant versus benign chondroid syringoma. Five chondroid syringoma tissue samples were analyzed -2 aggressive and 3 benign. Immunostaining for tumor suppressor genes p16 and p53 was performed. Genomic DNA was isolated and genetic analysis was performed using a custom Sequenom MassArray. Chondroid syringomas with clinically aggressive behavior showed strong nuclear p16 expression in contrast to those with benign behavior. Both the malignant and benign chondroid syringomas demonstrated positive p53 expression with varying intensity. No somatic mutations were identified in any of the chondroid syringomas.