Purpose Homologous recombination (HR)-deficient breast tumors may have genomic alterations that predict response to treatment with PARP inhibitors and other targeted therapies. Methods Comprehensive molecular profiles of 4647 breast tumors performed at Caris Life Sciences using 592-gene NGS were reviewed to identify somatic pathogenic mutations in HR genes ARID1A, ATM, ATRX, BAP1, BARD1, BLM, BRCA1/2, BRIP1, CHEK1/2, FANCA/C/D2/E/F/G/L, KMT2D, MRE11, NBN, PALB2, RAD50/51/51B, and WRN, as well as 41 markers that may be associated with treatment response to targeted anticancer therapies. Results 17.9% of breast tumors had HR mutations (HR-MT, 831/4647) ER/PR+ , HER2− 18.3%, n  = 2183; TNBC 18.2%, n  = 1568; ER/PR+ , HER2+ 15.6%, n  = 237; ER/PR−, HER2+ 12.9%, n  = 217; unknown n  = 442. Mean TMB was higher for HR-MT tumors across subtypes (9.2 mut/Mb vs 7.6 h-wild type (HR-WT), p  ≤ 0.0001) and independent of microsatellite status. MSI-H/dMMR was more frequent among HR-MT tumors (2.1% HR-MT vs 0.2% HR-WT, p  ≤ 0.0001), as was tumor PD-L1 overexpression (13.2% HR-MT vs 11.0% HR-WT, p  = 0.08). Additional co-alterations were similar between HR-MT and HR-WT, with the exception of PIK3CA (30.3% HR-WT vs 26.4% HR-MT, p  = 0.024) and AKT1 (3.7% HR-WT vs 2.1% HR-MT, p  = 0.021). AR overexpression and PIK3CA mutations were more common among ER/PR+ tumors. ERBB2 mutations were seen in both HER2+ and HER2− tumors. Conclusions HR-MT was common across breast cancer subtypes and co-occurred more frequently with markers of response to immunotherapy (MSI-H/dMMR, TMB) compared to HR-WT tumors. Mutations were identified in both HR-MT and HR-WT tumors that suggest other targets for treatment. Clinical trials combining HRD-targeted agents and immunotherapy are underway and could be enriched through comprehensive molecular profiling.