This study examined molecular (DNA hypermethylation), clinical, histopathological, demographical, smoking, and alcohol variables to assess diagnosis (early versus late stage) and prognosis (survival) outcomes in a retrospective primary laryngeal squamous cell carcinoma (LSCC) cohort. The study cohort of 79 primary LSCC was drawn from a multi-ethnic (37% African American), primary care patient population, diagnosed by surgical biopsies in the Henry Ford Health System from 1991-2004, and followed from 5-18 years (through 2009). Of the 41 variables, univariate risk factors of p<0.10 were tested in multivariate models (logistic regression {diagnosis} and Cox {survival} models {p<0.05}). Aberrant methylation of ESR1 (p=0.01), race as African American (p=0.04), and tumor necrosis (extensive) (p=0.02) were independent predictors of late stage LSCC. Independent predictors of poor survival included presence of vascular invasion (p=0.0009), late stage disease (p=0.03) and methylation of the HIC1 gene (p=0.0002). Aberrant methylation of ESR1 and HIC1 signified independent markers of poorer outcome. In this multi-ethnic, primary LSCC cohort, race remained a predictor of late stage disease supporting disparate diagnosis outcomes for African American patients with LSCC.