Background: The somatic mutation HSD3B1(1245A>C) has been mechanistically linked to castration-resistant prostate cancer by encoding a mutant enzyme that augments intratumoral dihydrotestosterone synthesis. Given the HSD3B1(1245C) allele is also frequently found in the germline, we hypothesized men inheriting this variant allele would exhibit resistance to androgen deprivation therapy (ADT), as manifested by worse clinical outcomes. Methods: We used a prospectively maintained prostate cancer registry to identify men treated with ADT for biochemical failure in the post-prostatectomy setting who were without evidence of metastatic disease at the time of ADT initiation. We analyzed progression-free survival, distant metastasis-free survival, and overall survival according to HSD3B1 genotype using Kaplan-Meier methods. Cox proportional hazards regression was performed to evaluate potential gene-dosage effects, with homozygous wild-type men serving as the reference group. Demographic and treatment characteristics were compared across genotypes to assess for possible confounders using Fisher’s exact test and Kruskal-Wallis analysis of variance. Results: Of 118 men genotyped, 37% were homozygous wild-type, 53% were heterozygous, and 10% were homozygous variant. Demographic and treatment characteristics did not differ across groups. Median progression-free survival diminished as a function of the number of variant alleles inherited (6.6 years in homozygous wild-type men, 4.1 years in heterozygotes, and 2.5 years in homozygous variant men; P=0.01). Median distant metastasis-free survival likewise decreased according to the number of variant alleles inherited (9.1 years in homozygous wild-type men, 6.8 years in heterozygotes, and 3.6 years in homozygous variant men; P=0.01). Finally, overall survival also diminished with the number of variant alleles inherited (5-year and 10-year overall survival: 82% and 55% in homozygous wild-type men, 74% and 35% in heterozygotes, and 58% and 0% in homozygous variant men; P=0.006). Conclusions: Inheritance of the variant HSD3B1(1245C) allele that enhances dihydrotestosterone synthesis may predict resistance to ADT for prostate cancer. These findings require validation.