To inform novel personalized medicine approaches for race and socioeconomic disparities in head and neck cancer, we examined germline and somatic mutations, immune signatures, and epigenetic alterations linked to neighborhood determinants of health in Black and non-Latino White (NLW) patients with head and neck cancer. Cox proportional hazards revealed that Black patients with squamous cell carcinoma of head and neck (HNSCC) with PAX5 (P ¼ 0.06) and PAX1 (P ¼ 0.017) promoter methylation had worse survival than NLW patients, after controlling for education, zipcode, and tumor-node-metastasis stage (n ¼ 118). We also found that promoter methylation of PAX1 and PAX5 (n ¼ 78), was correlated with neighborhood characteristics at the zip-code level (P < 0.05).Analyses also showed differences in the frequency of TP53 mutations (n ¼ 32) and tumor-infiltrating lymphocyte (TIL) counts (n ¼ 24), and the presence of a specific C ! A germline mutation in JAK3, chr19:17954215 (protein P132T), in Black patients with HNSCC (n ¼ 73; P < 0.05), when compared with NLW (n ¼ 37) patients. TIL counts are associated (P ¼ 0.035) with long-term (>5 years), when compared with short-term survival (<2 years). We show bio-social determinants of health associated with survival in Black patients with HNSCC, which together with racial differences shown in germline mutations, somatic mutations, and TIL counts, suggests that contextual factors may significantly inform precision oncology services for diverse populations. A, Molecular markers, combined with external and internal environment variables, can be used as biosocial markers of head and neck cancer outcome disparities, head and neck cancer markers, and precision medicine markers for patients with head and neck cancer. B, Shows that PAX5 methylation levels inversely correlate (r ¼ À0.83) with TIL counts in patients with HNSCC. C, Shows that JAK3 expression in Black patients with HNSCC differs by anatomic location. D, Shows that Notch1 mutations and PAX1 methylation levels also differ by anatomic location and race in patients with HNSCC.