Purpose The present study evaluated tumor-infiltrating lymphocytes (TILs) based on standardized scoring method and investigated its predictive value for axillary pathologic complete response (apCR) and prognostic significance for event-free survival (EFS) in neoadjuvant-treated HER2-positive breast cancer with initially biopsy-proven nodal metastasis. Methods We assessed TILs in a total of 187 pretherapeutic core biopsies of primary tumors. Receiver operating characteristic curve analysis was conducted to calculate the optimal cut-off point of TILs in discriminating axillary pathologic response. The associations of TILs with apCR or EFS were investigated by univariate and multivariate analyses. Results Receiver operating characteristic curve analysis identified a 10% cut-off point of TILs that optimally discriminated apCR from non-apCR (P < 0.001). High TILs were determined as TILs >= 10%, and tumor with TILs < 10% was defined as lymphocyte-depleted breast cancer (LDBC). The apCR rate of the entire cohort was 66.3% (124/187). Tumors with high TILs had a significantly higher apCR rate compared with LDBC (78.5% vs. 43.9%; P < 0.001). High TILs (P < 0.001), breast pathologic complete response (P = 0.006), and negative status of hormone receptor (P = 0.021) were independent predictors for apCR. High TILs were a markedly powerful predictor with an odds ratio of 4.01 (P < 0.001). EFS was significantly better among patients with high TILs than among those with LDBC (P < 0.001). Univariate and multivariate analyses indicated that high TILs (P = 0.019) and apCR (P = 0.013) were independent predictors for favorable EFS. Conclusions TILs have predictive value for apCR and prognostic significance for EFS in initially node-positive and HER2-positive breast cancer treated with neoadjuvant therapy. LDBC (TILs < 10%) has a significantly unfavorable impact on apCR rate and EFS.