Background: Several trials have confirmed that pathologic complete response (pCR) rates after neoadjuvant chemotherapy (NAC) are significantly lower in HER2+/ER+ patients (pts) than in HER2+/ER− pts. To elucidate this phenomenon, we investigated the association of anti-apoptotic Bcl-2, which is frequently overexpressed in ER+ tumors, with to NAC resistance. Methods: Pretreatment formalin-fixed tumor tissues were collected from 75 HER2+ pts receiving NAC comprising anthracyclines, taxanes, and trastuzumab. mRNA expression was detected by PCR amplificationand quantitative primer extension using MassARRAY (Sequenom, CA). The panel of 15 genes comprised EGFR, HER2, HER3, IGF1R, FGFR, PTEN, INPP4B, SRC-1, DUSP4, ESR1, PgR, FOXA1, PDL1, CTLA-4, and Bcl-2, whose expressions were dichotomized according to median values. PIK3CA mutations were detected using MassARRAY genotyping. ER, PTEN, and Bcl-2 protein expressions were scored from 0 to 3 according to the frequency and intensity by immunohistochemisty (IHC). The relationship between variables was assessed by Spearman's correlation. Logistic regression analysis was performed to detect predictors of pCR, which was defined as no invasive tumor in the breast or axilla. Results: Median age was 58 years; 97% were stage II–III, 47% were ER+, and 52% (40%/ 63% in ER+/ ER−) achieved pCR. Bcl-2 mRNA and protein expression were correlated (r=0.66, p=.001). In univariate analysis, pCR was associated with high mRNA levels of ESR1, PgR, IGF1R, HER2, CTLA4, PDL-1, and Bcl-2 (p≤.05), but not with PIK3A mutations or PTEN loss by IHC. Bcl-2 expression was significantly correlated with ESR1 (r=0.74), PgR (r=0.74), and IGF1R (r=0.68); thus, PDL-1, CTLA4, HER2, and Bcl-2 were tested in the multivariate model. Bcl-2 retained the predictive value for pCR [p=.022; odds ratio (OR), 0.28 (0.10–0.84)]. In ER+ pts, median Bcl-2 levels were 2.2 times higher than in ER− pts, and pCR rates were 17% and 65% in pts with high and low Bcl-2 expression, respectively (p=.006; OR, 0.11). Conclusions: Our data suggests Bcl-2 expression is predictive of pCR and provides a rationale for the evaluation of Bcl-2 inhibitors in HER2+/ER+ BC pts.