Background: Circulating tumor DNA (ctDNA) can be used to identify mutations and amplifications in patients with prostate cancer (PC). Identification of actionable mutations in BRAF may allow the use of targeted therapeutics not typically used in prostate cancer. Methods: We analyzed a ctDNA-based genomic profile database (Guardant Health) with 2274 unique advanced-stage patients, and a tissue-based genomic database (TCGA) with 3178 unique patients (73% locoregional, 27% metastatic). We compared the frequency and types of BRAF anomalies found in those datasets. We calculated the odds ratio of observing other genetic anomalies based on the BRAF mutation and amplification status. Finally, we utilized Principal Component Analysis (PCA) to study the utility of BRAF as a discriminator in identifying genetic subtypes of PC. Results:BRAF missense mutations in PC were found in 3.34% of the 2274 patients in the ctDNA cohort and in 1.1% of the 3178 patients in the TCGA cohort. Variants of Uncertain Significance (VUS) mutations were more commonly identified by ctDNA (53.8% of all mutations) vs TCGA (16.1% of all mutations). Biologically-significant mutations of all classes (I, II, III) were found in both datasets. BRAF mutations were mainly non-V600E and most mutations were clonal. Significant mutations common to both the ctDNA and TCGA cohorts include K601E, G469A, D594G, V600E, G466E, G446R, Q257K, I300V and R271H. Mutations unique to either ctDNA or TCGA datasets were found as well. BRAF mutations are highly associated with additional mutations in CDKN2A, TERT, and KRAS, as well as amplifications of CCNE1, KRAS, CDK6 (p < 0.01). BRAF amplifications are highly associated with multiple other gene amplifications, and with AR mutations (p < 0.01). Tumors with BRAF mutations and with BRAF amplifications are genetically distinct, and PCA indicates that BRAF status accounts for a significant amount of the difference. We described two patients that were treated with MEK targeted therapy with treatment response. Conclusions: 1. The use of ctDNA-based genomic analysis identified BRAF anomalies with a higher frequency than tissue-based techniques, but this is mostly due to higher numbers of VUS mutants found with ctDNA. Biologically significant BRAF mutations are mostly clonal and non-V600E mutations. 2. BRAF mutations and amplifications are associated with other specific gene anomalies. 3. ctDNA is a useful tool for identifying the genomic profile of PC in the clinical setting. 4. PC subjects with BRAF mutations identified by ctDNA may respond to MEK inhibitor therapy.