Background: Circulating tumor-derived DNA (ctDNA) is an accessible method for characterizing tumoral alterations. We report ctDNA screenings of mCRPC patients (pts) who have had germline testing. Methods: Guardant360 (Guardant Health, Inc.) assesses ctDNA using sequencing to identify genomic alterations in 73 cancer-related genes. Alterations were categorized by type which included amplifications, deletions, frameshift mutations, insertions, missense mutations, splice mutations, truncations, and other. A total of 186 PCa pts in various stages of therapy had both ctDNA and germline DNA tested. Results: Of the 186 pts tested for germline mutations, 26 (14%) were germline positive. The most common germline mutation was BRCA2 with 12 (46%) pts, followed by ATM with 3 (11%). Of the total gene alterations were detected on ctDNA analysis of germline positive pts, with the most common genes being TP53 (n = 14/73, 19%), NF1 (n = 6/73, 8%), PIK3CA (n = 6/73, 8%), and BRCA2 (n = 5/73, 7%). Of the total gene alteration were detected on ctDNA analysis of germline negative pts, with the most common genes being TP53 (n = 94/588, 16%), AR (n = 90/588, 15%), EGFR (n = 31/588, 5%), and BRAF (n = 29/588, 5%). Germline negative pts showed had more amplifications (p = 0.008) while germline positive patients had more frameshift mutations (p = 0.025). Other alterations (deletion, missense, insertion, other, splicing, and truncating) were not significantly different. Missense mutations were the most prevalent type of gene alteration in germline negative (n = 306/609, 44%) and germline positive (n = 45/77, 48%), followed by amplifications (n = 210/609, 25% germline negative and n = 15/45, 18% germline positive). The median percent ctDNA values for missense mutations in germline negative and positive patients were 0.5% and 0.3% respectively. Of the germline positive pts, BRCA2 mutation was associated with the highest number of genes with alterations (n = 39), followed by RECQL4 (n = 8), ATM (n = 5), and MSH2 (n = 5). Conclusions: Germline positive pts had a higher number of frameshift mutations compared to germline negative pts. Additionally, pts with BRCA2 had the highest number of genes altered in ctDNA.