Abstract Background: Racial disparities in lung cancer exist, as African Americans (AAs) have the highest incidence of lung cancer and rate of lung cancer-related death and develop lung cancer at an earlier age compared with other racial groups. Multiple structural determinants of health affect poorer survival in AAs. In addition, evidence suggests that differences in tumor biology also contribute to disparities in clinical outcomes. This work addresses the urgent need to define further the molecular landscape of non-small cell lung cancer (NSCLC) in the AA population in order to drive novel biomarker and therapeutic development and ultimately improve clinical outcomes. Methods: We have analyzed differentially expressed genes (DEGs) and differentially spliced genes (DSGs) between resected formalin-fixed, paraffin-embedded lung squamous cell carcinoma specimens from 20 AA and 20 white patients (self-reported race) using Affymetrix Clariom D Assay, human and Transcriptome Analysis Console Software. To obtain genetically estimated indicators of race, we performed ancestral genotyping. After excluding specimens from biracial patients and those with positive versus negative area under the curve less than 0.6, we used a cohort of 14 specimens from AA patients and 13 specimens from white patients for analysis. Results: Transcriptome analysis revealed 450 DEGs and 7,089 DSGs, in which we identified 13,763 unique splicing events, between NSCLC in AA and white patients. The nuclear receptors meta pathway and the olfactory receptor pathway are over-represented with such DEGs. Seven of the DEGs also exhibit differential expression between lung squamous cell carcinoma in AA and white patients in The Cancer Genome Atlas (TCGA). Twenty-eight of the DEGs also exhibit differential expression between prostate cancer in AA and white patients. Among the 7,089 DSGs between NSCLC in AA and white patients, 599 also exhibit differential splicing between prostate cancer in AA and white patients, 33 also exhibit differential splicing in breast and liver cancer, and 6 also exhibit differential splicing in breast, liver and prostate cancer. Validation of prioritized genomic differences using polymerase chain reaction and investigation of the functional significance of prioritized genomic differences to lung cancer cell biology using CRISPR-Cas9 technology is currently under way. Conclusions: This study identifies novel aggregate gene expression and splicing differences between NSCLC in AA and white patients. Interestingly, the number of DSGs far exceeds the number of DEGs in the same tissues and a number of DEGs and DSGs exhibit differential aggregate gene expression and splicing, respectively, in additional solid tumor types. Upon further study, these mechanisms have the potential to serve as novel targets for the development of biomarkers or therapeutic agents for lung cancer, and to reduce the mortality burden from lung cancer among AAs. Citation Format: April E. Deveaux, Dadong Zhang, Muthana Al Abo, Nadine J. Barrett, Rick A. Kittles, Kouros Owzar, Shannon J. McCall, Jeffrey Crawford, Steven R. Patierno, Jeffrey M. Clarke, Jennifer A. Freedman. Genomic differences between non-small cell lung cancer (NSCLC) in African American and white patients [abstract]. In: Proceedings of the Eleventh AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2018 Nov 2-5; New Orleans, LA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl):Abstract nr B071.