Abstract Esophageal adenocarcinoma is the most common histological subtype of esophageal cancer in Western countries and shows poor prognosis with rapid growth. EAC is characterized by a strong male predominance and racial disparity. EAC is up to five-fold more common among Whites than Blacks, yet Black patients with EAC have poorer survival rates. The racial disparity remains largely unknown, and there is limited knowledge of mutations in EAC regarding racial disparities. We used whole-exome sequencing to show somatic mutation profiles derived from tumor samples from eighteen EAC male patients. We identified three molecular subgroups based on the pre-defined esophageal cancer-specific mutational signatures. Group 1 is associated with age and NTHL1 deficiency-related signatures. Group 2 occurs primarily in Black patients and is associated with signatures related to DNA damage from oxidative stress and NTHL1 deficiency-related signatures. Group 3 is associated with defective homologous recombination-based DNA often caused by BRCA mutation in White patients. We found race-specific genes (White only: SMAD4, Black only: ERBB2, F5, PREX2, BRCA1, GATA4, and SCN10A). Our results provide valuable insights into understanding the underlying mutational mechanisms of EAC in Black and White racial sub-groups and could contribute to generating actionable targets for interventions and treatments.