Background: Liquid biopsy with plasma circulating tumor DNA (ctDNA) is a noninvasive alternative to tissue genomic profiling. The yield of ctDNA is largely dependent upon the total amount and proportion of ctDNA in the total circulating DNA pool. Factors that predict successful genomic profiling via liquid biopsy amongst Veterans with prostate cancer are unknown. Methods: 764 veterans with prostate cancer who received liquid biopsy testing between February 2019-2021 were selected from the VA National Precision Oncology Program (NPOP) database. Baseline patient variables including age at specimen collection date, race, PSA, PSA doubling time (PSADT), sites of metastatic involvement (i.e., bone, brain, liver, lung, and lymph nodes), number of metastatic sites, Gleason score, and Gleason grade group were extracted from the VA Corporate Data Warehouse (CDW). Two independent approaches were used to define a successful liquid biopsy: Approach 1: Liquid biopsies with an alteration detected in one or more prostate cancer related genes (AR, CDK12, SPOP, MED12, CCND1, BRAF, AKT1, TMPRSS2) (n = 337); Approach 2: Liquid biopsies with alterations detected in any gene detected by the Foundation One Liquid CDx assay (n = 670). We performed univariate and multivariate logistic regression analysis for Odds Ratio (OR), 95% confidence interval (CI), and conducted statistical significance tests to investigate associations between clinical factors and liquid biopsy test outcome. P-value < 0.05 was considered significant. Results: In Approach 1, the OR by univariate analysis was 4.80 (P < 0.001; 95% CI [3.09, 7.47]) for 4th PSA quantile group versus 1st PSA quantile group. The OR was 3.61 (P < 0.001; 95% CI [2.0, 6.5]) for PSADT less than 3 months versus PSADT more than 60 months; brain metastasis had the highest OR value among metastatic sites of 2.47 (P = 0.008; 95% CI [1.27. 4.8]). In multivariate analysis, PSA, PSADT and sites of metastasis remained significant risk factors. Statistical significance tests indicated PSA, PSADT, and sites of metastasis were significantly different between the success and failure groups. In Approach 2, no statistically significant associations were observed between the studied variables and any outcome. Conclusions: Factors such as PSA, PSADT, and metastatic site were significantly associated with a successful liquid biopsy of detecting prostate cancer related gene mutations, while the outcome of detecting any gene mutations was not statistically significant associated with studied variables in this study population. Given the likelihood that a significant number of non-prostate cancer mutations are likely due to clonal hematopoiesis, this finding is expected. Our findings may facilitate clinical decisions around genomic profiling by liquid biopsies in the absence of tumor tissue, thereby increasing the success rate of sequencing efforts for treatment selection.