The manifestations of colorectal cancer (CRC), including its incidence, morbidity, and mortality, demonstrate large disparities between recognized race and ethnic populations in the US and are particularly worse among Black and Native American individuals.¹ Understanding and quantifying contributing factors for the disparities may help direct approaches to mitigate them, improving detection of early disease at a curable stage and augmenting patient survival for all races and ethnicities after CRC is detected and treatment is initiated.^2,3 In JAMA Oncology, Yousef et al⁴ examined clinical, socioeconomic, and cancer tissue molecular data obtained from more than 47 000 patients with CRC cared for at a single institution from 1973 to 2023 to quantify contributions of each of these features toward the observed disparities. Black patients with CRC, compared with non-Hispanic White patients with CRC, presented at a younger age, had more right-sided colon cancers, presented at more advanced disease stage, and showed shorter overall survival (hazard ratio, 1.16), consistent with prior data. During 5 decades, overall survival improved for individuals of all race and ethnicity groups but at different rates, with Black patients with CRC showing a widening disparity compared with non-Hispanic White patients with CRC from 2018 to 2023 than all prior time periods. Black patients with CRC had lower socioeconomic status as measured by the Area Deprivation Index and demonstrated worse health performance status as measured by Eastern Cooperative Oncology Group scores among the races and ethnicities examined. Tumor molecular analysis revealed Black patients with CRC, compared with non-Hispanic White patients with CRC, showed lower frequency of microsatellite instability (MSI-high), higher variant frequency of APC, KRAS, and PIK3CA, and lower variant frequency of BRAF and KIT. Through mediation analysis, the positive relative contribution toward the observed disparity for overall survival between Black and non-Hispanic White patients with CRC was (1) Area Deprivation Index for +29% of the effect, (2) location in the colon for +8.7% of the effect, (3) marital status for +3.9% of the effect, (4) age at diagnosis for +2.2% of the effect, and (5) molecular features of MSI-high status (+4.9%), BRAF variant (+3.4%) and KRAS variant (+1.8%) for a combined +10% of the effect. APC variant (−5.8%) and Eastern Cooperative Oncology Group performance status (−8%) were negative covariates for survival disparity. Overall in the study by Yousef et al,⁴ adjustment of all socioeconomic, clinical, and molecular covariates that were examined explains 39% of observed racial and ethnic survival disparity.