Background: The presence of high TILs has been implicated as a predictor of pathologic complete response (pCR) and decreased recurrence rates in BC patients. However, there is conflicting data for the benefit of T in the adjuvant setting for HER2 positive (HER2+) BC patients with high TILs. In addition, greater numbers of CD68 (+) cells (macrophage marker) in tumor stroma has been shown to be an independent prognosticator for reduced BC specific survival. Methods: Core biopsies from52 Her2+ BC patients treated with neoadjuvant (NAT) chemotherapy with or without T were identified. Two pathologists independently quantified stromal TILs and CD68 ratio (inside the TILs population) using Hematoxylin/Eosin and immunohistochemistry respectively. The association of TILs and CD68 with pCR rates was determined by Mann-Whitney U, Chi-square or Fisher’s exact test. Prognostic significance of TILs and CD68 ratio on pCR rates, disease free survival and overall survival (OS) was assessed by Kaplan-Meier analysis and log-rank test. Results: The median age and follow up for the cohort were 52 and 2.8 years, respectively. In the NAT setting, 40 patients received conventional chemotherapy and T (77%) and 12 patients were treated with chemotherapy alone (23%). Overall the pCR rate in the studied population was 40%. Eight patients (15%) had high levels of TILs ( ≥ 60%) and 20 patients (38%) had low CD68 ratio ( ≤ 60%). A high percentage of TILs was significantly correlated to low CD68 ratio (p < 0.0001). High levels of TILs and low CD68 ratio were each associated with greater pCR rates for the cohort of patients who received NAT T, respectively (p = 0.05, p = 0.03). Furthermore, pCR was predictive of better OS (p = 0.02) for the patients treated with NAT T. However, these associations were no longer significant when we performed the analysis on the whole population (p = 0.09, p = 0.32). Conclusions: Our results show that high levels of TILs are associated with low CD68 ratio, and both are predictors of pCR in patients with HER2+ BC receiving NAT T. Importantly, pCR as determined by CD68 and TILs translated into an OS benefit. TILs and CD68 ratio represent potential prognostic and predictive markers in patients with HER2+ BC.