Objective: To assess the role of family history (FH) in the risk of a positive prostate biopsy (PBx) in a large North American biopsy population as earlier reports showed increased risk of prostate cancer (PCa) in men with a FH, but the risk has been limited to low grade prostate cancer in smaller studies, and the REDUCE trial found no such risk in North American patients. Methods: We evaluated 4360 men undergoing initial extended biopsy (8-14 cores). Indications were elevated prostate-specific antigen (PSA) and/or abnormal digital rectal examination (DRE). Variables including age, FH of PCa, race, PSA, and DRE results were included in our analysis to assess risk factors associated with PCa, high-grade prostate cancer (HGPCa), and low-grade prostate cancer (LGPCa). Results: Two hundred sixty-eight patients had an FH of PCa whereas 4092 had negative FH. Positive biopsy was found in 1976 patients with HGPCa in 1149 and LGPCa in 827. Among 268 patients with an FH, overall PCa was found in 144 of 268 patients (54%); HGPCa in 79 of 144 patients (55%) and LGPCa in 65 of 144 patients (45%). FH was a significant risk factor for PCa, HGPCa, and LGPCa in univariate and multivariate analysis (P =.0001,.02, and.02, respectively). Also, FH was associated with high-risk benign pathology in the form of atypical small acinar cell proliferation (ASAP) or high-grade prostatic intraepithelial neoplasm (HGPIN) (P =.04). Conclusion: Men in North America with an FH of PCa who undergo prostate biopsy are more likely to be diagnosed with both HGPCa and LGPCa.