Background: To assess if partial vs whole breast irradiation (RT) in treatment of the various biological (bio-) subtypes of breast cancer would lead to differing clinical results, a match pair analysis of APBI vs WBI was undertaken. Methods: Between 3/1993 and 9/2013 all breast CA patients (pts) treated at one institute with either APBI or WBI were matched 1:1 by follow-up (FU) +/- 15 yrs, stage and bio-subtype. This yielded 772 pts of whom 640 were luminal A, 42 luminal B, 58 triple neg (TNBC), 6 HER2+, and 26 triple +. Outcomes were analyzed across the various bio-subtypes for all the pts (APBI + WBI), APBI alone and WBI alone. The endpoints assessed were local recurrence (LR), true recurrence/marginal miss (TR/MM), elsewhere failure (EF), regional recurrence (RR), distant metastasis (DM), disease-free survival (DFS), and contralateral breast failure (CLBF). Results: Mean age was 66 (32-94) with a mean FU of 5.2 years (0.1-18.3). Regarding systemic therapy, 75% received endocrine Rx, while chemotherapy was documented in 21%. For all pts (APBI+WBI) there was no significant difference across the various bio-subtypes with respect to 5, 10 and 15 yr actuarial LR, TR/MM, EF, RR, DM, DFS and CLBF. Likewise, for the 386 APBI-alone treated pts, no significant difference was found between the various bio-subtypes for all the same endpoints reported. However, for the 386 WBI pts, a significant difference was seen in the 15-year actuarial LR between luminal A and TNBC (1.5% vs 7.4%, p = 0.007). Significance was also found in the 15-year actuarial DFS between luminal A/B and TNBC (98.0%, 95.2%; 86.0%, respectively, p = 0.009). Conclusions: In comparing partial to whole breast RT across the various biological subtypes of breast CA, APBI is at least as effective as WBI. However, the retrospective nature of this study along with the limited numbers of pts in the HER2+ and triple + subsets are weaknesses which are acknowledged to exist in this dataset. The addition of further pts in all the biological subtypes, particularly the HER2+ and triple + subsets, along with results from randomized trials incorporating biomarker data will be needed to substantiate these findings.