Background: Sex differences in cancer incidence are pronounced, with men having 2-3 times the rate of most non-reproductive cancers than women. However, whether the male predominance is due to differences in biological factors or behavior remains not well understood. This study investigated sex differences in cancer incidence by race and ethnicity to provide a greater understanding of whether differences are driven by biological factors or environmental exposures. Methods: Cancer incidence data from the Surveillance, Epidemiology and End Result (SEER) program (2000-2019) was used to calculate male-to-female incidence rate ratios (MF IRR) for each cancer site and histological subtype, stratified by race and ethnicity (non-Hispanic White, non-Hispanic Black, non-Hispanic Asian/Pacific Islander, American Indian/Alaskan Native, and Hispanic), and age-standardized to the 2000 U.S. population for individuals ages ≥20 years. Results: Most non-reproductive cancers had a male predominance across race and ethnicity, with the largest MF IRR seen for cancers of the tonsil, hypopharynx, larynx, and Kaposi sarcoma (MF IRR > 4). Three cancers, gallbladder; peritoneum, omentum, mesenter; and thyroid, were more common among females than males across all race and ethnicity. Females had a higher incidence of anal cancer than males for all racial and ethnic groups except for non-Hispanic Black individuals where the MF IRR was >1. Cancers of the stomach, skin (excluding basal and squamous cell), melanoma skin, and other non-epithelial, and myeloma had greater MF IRR among non-Hispanic White adults than all other racial and ethnic groups. Non-Hispanic Black individuals had higher MF IRR of cancers of the liver and lung and bronchus, compared to other racial and ethnic group. Non-Hispanic White males had the highest MF IRRs for esophagus adenocarcinoma and gastric cardia adenocarcinoma and the lowest MF IRR for esophagus SCC compared to other races and ethnicity. Conclusions: The MF IRR for most cancers in this study did not differ by race and ethnicity, suggesting the influence of biological factors. Differences in the MF IRR across race and ethnicity may indicate carcinogenic exposure differences leading to the development of non-sex-specific cancers. Further research is needed to identify biological drivers of cancer incidence for most non-reproductive cancers. Funding: Intramural Research Program of the Division of Cancer Epidemiology and Genetics in the National Cancer Institute, National Institutes of Health.