Primary malignant melanomas of the squamous mucosa of the head and neck are rare. To learn more about the prognostic significance of various histologic parameters we examined the pathologic features of squamous mucosa from 40 patients seen at a single institution and correlated them with clinical outcome. Follow-up information was available on 37 patients. Thirty-five were treated with surgical resection and two were treated with radiotherapy. Twenty-six were dead at follow-up. Twenty-one of them died of disease. The interval between diagnosis and death ranged from 1 month to 16.5 years (median survival, 2.4 years). Eleven patients were alive at 4 months to 19.5 years after the diagnosis: six of them with disease and five of them free of disease (mean follow-up, 3.5 years). Predictors of poor survival by univariate analysis were the presence of vascular invasion (overall survival, p = 0.007; disease-specific survival, p = 0.01), a polymorphous tumor cell population (overall survival, p = 0.007; disease-specific survival, p = 0.008), and necrosis (overall survival, p = 0.007; disease-specific survival, p = 0.056). However, because these three parameters were associated with each other, none of them remained of independent predictive value for outcome by multivariate analysis. No prognostic significance was found for tumor thickness, level of invasion, ulceration, mitotic index, or nerve/nerve sheath involvement. Thus, the histologic parameters relevant for the prognosis of squamous mucosa differ significantly from those of cutaneous melanomas.