21 Background: Studies have shown that Black patients receiving chemoradiation (CRT) for locally advanced rectal cancer (LARC) have achieved clinical outcomes less satisfactory than those achieved by other racial groups, but the source of this disparity is poorly understood. This study investigated the demographic, geographic, socioeconomic, and clinical factors that underlie this disparity. Methods: We interrogated the National Cancer Database from 2004-2017 to identify patients with T3-T4 or N > 0 LARC treated with CRT prior to surgery. Response to CRT was determined by the rates of pathologic complete response (pCR) and tumor downstaging after treatment. Univariate analysis (UVA) was performed with chi-square and Fisher’s exact tests. Multivariate analysis (MVA) was then used to identify independent factors associated with improved pCR. Results: A total of 37,783 patient records were reviewed for the study (7.8% Black, 86.0% White, 6.1% Other). Black patients were younger (p < 0.0001), more often female (p < 0.0001), and more likely to live in metropolitan areas (p < 0.0001). LARC in Black patients was diagnosed at a higher clinical stage (p = 0.0007) and was more often treated with abdominoperineal resection in preference to low anterior resection (p < 0.0001). Black patients were more often uninsured or covered by Medicaid (p < 0.0001) and less often covered by commercial insurance (p < .0001). UVA demonstrated that Black patients achieved pCR and tumor downstaging at lower rates than White patients (11.6% vs 14.5%; 46.9% vs 51.8%, both p < 0.0001). On MVA, Black race (OR 0.8015, 95%CI 0.7101-0.9047), a rural location (OR 0.8211, 95% CI 0.7082-0.952), absence of commercial medical insurance (Medicaid OR 0.8394 95% CI 0.7456-0.9449; Medicare OR 0.8989 95% CI 0.8226-0.9823; No Insurance OR 0.6107 95% CI 0.5103-0.7309), and higher tumor grade and stage remained independent risk factors for a lower pCR. Additional significant unfavorable prognostic factors for pCR included younger age, male sex, lower hospital treatment volume, and higher tumor grade or stage. Similarly, Black race, lower hospital treatment volume, absence of commercial medical insurance, and higher grade or stage were significant unfavorable prognostic factors for downstaging. Neither lower income nor fewer years of education was associated with pCR or tumor downstaging. Conclusions: The results confirm a lower rate of response to CRT in Black patients with LARC. The identification of race as an independent risk factor after adjustment for sociodemographic, geographic, and clinical factors suggests that other unknown variables–including genetic differences unaddressed in this study–must be pursued comprehensively in future studies. The more advanced stage of rectal cancers in Black patients suggests that critical evaluation of current cancer screening methods may play a role in this effort.