Studies of the immunohistochemical profiles and clinical course of desmoplastic melanoma have produced conflicting results. We identified 28 cases of desmoplastic melanoma after a search of our files for spindle cell neoplasms of the head and neck from 1960 through 1995. The 17 male (61%) and 11 female (39%) patients averaged 65 years of age. The cheek was the most common location (12 cases, 43%). The average length of follow-up was 5 years. Overall 5-year survival rate was 46%. Melan A and tyrosinase positivity (P = 0.0195), smooth muscle actin positivity (P = 0.0328), tumor size (P = 0.0297), and tumor thickness (P = 0.0419) were significantly associated with local progression-free survival. No histologic or immunohistochemical marker was associated with overall or metastasis-free survival.