Background: Multi-gene hereditary cancer testing is common in prostate cancer (PC). We assessed the frequency of pathogenic mutations (mt) and examined associations with family history (FH), cancer recurrence, and overall survival (OS). Methods: Men with clinically localized or metastatic PC consented to germline DNA testing using a validated panel of 30 genes associated with elevated risk for common cancers (Color Genomics). Chi-square test and Fisher’s exact test were used to compare pathogenic mt and clinical characteristics. The Kaplan-Meier method was used to evaluate the associations of mt status with PSA recurrence and OS. Results: 315 men (median age 69, range 38-89) were included; 140 (44.4%) with localized and 175 (55.6%) with metastatic PC. 215 (68.3%) reported a FH of any cancer in one and 101 (32.1%) in ≥ 2 first-degree relatives. Genomic testing detected 12.1% of pts possessed a pathogenic mt (39 mt in 38 pts): BRCA2 (n = 12, 3.8%), CHEK2 (n = 10, 3.2%), APC (n = 7, 2.2%), MUTYH (n = 3, 0.9%), ATM (n = 2, 0.6%), and 1 each (0.3%) with NBN, PALB2, RAD51D, MSH2, and PMS2. Variants of uncertain significance were detected in 52 (16.5%). Men with FH of prostate, breast, ovarian, pancreatic cancer or/and melanoma (182/315, 58%), were more likely to have BRCA2 pathogenic mt (P = 0.049). Median age of diagnosis was 55 with BRCA2 versus 62 in non-carriers (P = 0.01). No association was found between FH of Lynch-associated cancers (colon, endometrial, gastric) and mismatch repair gene variants. The prevalence of pathogenic mt was significantly higher with visceral metastases (P = 0.001) but did not differ between localized and advanced PC pts (P = 0.602). In men with clinically localized PC at diagnosis (n = 226, 71.7%), pathogenic mt were associated with a shorter time to recurrence (30 vs 53 months, P = 0.004). Men with advanced PC (n = 175) and germline APC or MUTYH mt had worse median OS (44 vs 318 months, P = 0.004). Conclusions: Our findings confirm the incidence of men with non-PC FH associated with DNA repair gene mt and support testing in early stage pts. Further, our data support the prognostic significance of germline genetic alterations which deserves study in a larger cohort of pts.