Background: Male BC accounts for < 1% of all BC and is often diagnosed at later stage, which can result in higher mortality. Due to the rarity of this diagnosis, limited data exist on genomic alterations and prevalence of cancer susceptibility genes (CSG). We aimed to comprehensively describe the genomics of male BC and compare these to a FBC cohort across subtypes to provide insight on tumor biology and opportunities for targeted therapies. Methods: 275 male BC TBx or LBx were sequenced by Foundation Medicine (FM) using hybrid capture-based CGP. Both TBx and LBx were evaluated for all classes of genomic alterations (GA). Histological subtype, receptor status, and biopsy site were extracted from pathology reports. Paired samples with both TBx and LBx were available in 7 cases. The male BC TBx cohort with known receptor status (n = 253) was compared to a FBC cohort (n = 2855). Mutational prevalence in 5 breast CSG (ATM/BRCA1/BRCA2/CHEK2/PALB2) were compared along with their associated genomic LOH (gLOH) values. Results: Among male BCs, subtype distribution was: ER+/HER2- n = 210 (83%), ER+/HER2+ n = 22 (9%), TNBC n = 20 (8%). ER+/HER2+ male BC cases had higher rates of ERBB2 SV (22.7% v. 0.62%, p < 0.0001), PIK3CA (68.2% vs. 34%, p = 0.01), MDM2 amplifications (36% v. 4%, p < 0.0001) and GATA3 (36.6% v. 6.2%, p = 0.0002) than ER+/HER2+ FBC. In the ER+/HER2- cohort, male BC had more alterations in BRCA2 (13.8% v. 5.3%, p < 0.0001) and GATA3 (26% vs. 15%, p = 0.0004) and less alterations in TP53 and ESR1 (p < 0.0001 both). 28.6% of male BC v. 16.6% of FBC (p = 0.004) had one or more variants in one of 5 CSG of potential germline origin with a higher % of BRCA mutations in male BC vs. FBC (17.5% v. 9.9%, p = 0.0006). In the paired male BC Bx’s we saw genomic heterogeneity in a case showing 5 unique ESR1 alts and a PIK3CA SV unique to LBx done at the same time as TBx. We saw evidence of resistance with a shared BRCA1 alteration and several reversion mutations unique to LBx taken 471 days later, and a longitudinal pair with unique ESR1,PIK3CA and MTOR mutations in a LBx 547 days apart. Conclusions: Although male and female BC share some common alterations, our study revealed potentially important findings that may explain biological differences and provide treatment opportunities. Despite HR+/HER2+ male BC being rare, it was notable for increased co-mutations with ERBB2 SV, PIK3CA SV, and GATA3 SV, which can be associated with a worse prognosis but perhaps allow more novel combinations. ESR1 mutations appear more common in ER+/HER2- FBC reflective of treatment with aromatase inhibitors versus tamoxifen for male BC. TP53 mutations were more common in all subtypes of FBC. BRCA2 mutations and other potential germline CSG variants were more common in male BC, suggesting an opportunity for PARP inhibitors. LBx identified additional biomarkers and resistance mutations not seen in TBx.