Background: African American (AA) men are underrepresented in prostate cancer (PC) trials but have a greater probability of both developing and dying from prostate cancer (PC) than other populations. CDK12 mutations in PC are associated with aggressive disease, increased metastasis, and decreased overall survival. Some preliminary data has suggested that CDK12 mutations may be more common in AA men. This study reports data from next-generation sequencing (NGS) of tissue from a large population of patients with PC in the real-world setting to investigate frequency of pathogenic CDK12 mutations in AA men and White men. Methods: De-identified records from patients with primary PC who underwent NGS with Tempus xT (solid tumor, 648 genes, 500× coverage, full transcriptome RNAseq for a subset of patients) were analyzed to characterize the frequency and types of pathogenic CDK12 mutations, and co-mutation in other assessed genes. Results were compared between patients identified as AA and White. Patients were excluded if they were Microsatellite Instability high (MSI-H), Tumor Mutational Burden (TMB) ≥10, or Mismatch Repair deficient (MMR-d). Results: Genomic profiles were analyzed from tissue samples of 6121 unique patients; of 3,555 patients with known race, 646 (18%) were AA, 2657 (75%) were White, and 252 (7%) were of other races. Of these patients, 3026 were AA or White after excluding 277 patients with known MSI-H, TMB≥10, or MMR-d status. AA were younger at diagnosis than Whites (median 63 vs 66 years; p<0.001). Tissue samples from AA men were significantly more likely than those from Whites to express a pathogenic CDK12 mutation (42 [7.2%] vs 93 [3.8%], p<0.001). The majority of the variants identified were truncating mutations. There were no differences in truncating vs. non-truncating alterations between White and AA men, nor were there differences in the prevalence or distribution of co-mutations between the two populations. Conclusions: AA men with PC show a higher frequency of pathogenic CDK12 mutations than Whites in a large real-world population. Co-mutations did not vary by race, and the alterations were most likely to be truncating mutations in both races.