Background: Patients with high-risk non-muscle-invasive bladder cancer (NMIBC) have heterogeneous outcomes with African Americans (AAs) having worse survival than European Americans (EAs). It is unknown whether race-based biological differences contribute to this disparity. Methods: We performed a retrospective cohort study including patients from the University of Texas Medical Branch (UTMB) and the Durham VA Health Care System (DVAHCS) from 2010-2020 among treatment naïve, high-risk NMIBC. Profiled gene expressions of high-risk NMIBC by race were performed using the UROMOL classification system. Results: A total of 26 patients (14 AAs and 12 EAs) matched on age and sex were included with no significant difference in clinical stage group (CIS +/- T1 or TaHG vs. TaHG or T1, no CIS), smoking status, or progression. We found a similar racial UROMOL subtype distribution with class 2a being most common. A total of 10 genes were discovered to be commonly upregulated differentially expressed genes (up-DEGs) in AAs vs EAs. EFEMP1, which has been associated with progression to muscle-invasive bladder cancer (MIBC) in vitro, and S100A16 gene expression, which has been implicated with mitomycin C resistance in bladder cancer in vitro, was significantly more common among AAs. We used single nuclei analysis to map the malignant cell heterogeneity in urothelial cancer which five distinct malignant epithelial subtypes whose presence has been associated with different therapeutic response prediction ability. We mapped the expression of the 10 genes commonly up-DEGs by race as a function of the five malignant subtypes. This showed borderline (p = 0.056) differences among the subtypes suggesting AA and EA patients may be expected to have different therapeutic responses to treatments for BC. AAs were enriched with immune-related, inflammatory, and cellular regulation pathways compared to EAs, yet appeared to have reduced levels of the aggressive C3 bladder tumor cell population. Conclusions: In this small sample, we found similar subtype distribution among high-risk NMIBC patients according to race. However, gene expression differs by race, supporting potential novel race-based etiologies for differences in muscle-invasion, response to treatments, and transcriptome pathway regulations. Further biological studies in NMIBC molecular sub-stratification, associated treatment(s), and prognoses in a larger cohort are needed to support these hypotheses.