Background: Genetic differences between African American and Caucasian patients with advanced prostate cancer may contribute to racial disparities in terms of treatment outcomes and survival, hence further exploration is warranted. We assessed ctDNA differences between African American and Caucasian men in the setting of CRPC post treatment with abiraterone and/or enzalutamide. Methods: From 2015 through 2022 at Tulane Cancer Center, 250 patients with CRPC including 50 African Americans and 200 Caucasian with prior abiraterone and/or enzalutamide treatment were included. All patients had ctDNA assessed via Guardant360. Data including both gene mutations and types of mutations were for between 73-80 genes. Clinical annotation including initial staging, treatment history, and genetic testing were obtained. Statistical analyses included Fisher’s exact test and Wilcoxon rank-sum test. Results: The most common pathogenic/likely pathogenic (P/LP) alterations in both African Americans and Caucasians were TP53 (44% and 46%, respectively), AR (50% and 39%), and PIK3CA (14% and 9%). CDK12 (OR= 8.955, 95% C.I. [2.156, 37.192], p=0.003) and KIT (OR= 5.710, 95% C.I. [1.235, 26.397]. p=0.031) alterations were more frequently detected in African Americans. In terms of pathologic mutation type, frameshift mutations were significantly more frequent in African Americans (OR= 2.293, 95% C.I. [1.103, 4.769], p=0.035). All patients were CRPC at the time of testing and had prior abiraterone and/or enzalutamide, but there were no significant differences between African American and Caucasian patients with regards to prior life-extending therapies. Conclusions: African Americans with CRPC post treatment with abiraterone and/or enzalutamide had a higher frequency of P/LP CDK12 and KIT mutations, which have both been shown to lead to aggressive clinical features and treatment resistance. African Americans also had a higher incidence of frameshift mutations, a finding not previously noted.