Purpose Neoadjuvant systemic treatment (NST) is increasingly administered in breast cancer patients. This study was conducted to identify predictors for tumor response in the breast and axilla. Methods All female patients with nonmetastatic, noninflammatory breast cancer receiving NST between 2003‐2013 at the Catharina Cancer Institute in Eindhoven, The Netherlands, were included. Results The majority of 216 of the 337 patients receiving NST (65%) presented with a cT2 tumor. In 159 patients (47%), the axilla was clinically node positive. A pathologic complete response (pCR) in the breast was achieved in 83 patients (24.6%), and a pCR in the axilla in 65 node‐positive patients (40.9%). The triple‐negative (OR 4.29, 95% CI 2.15‐8.55) and hormone receptor (HR)‐negative/HER2‐positive tumors (OR 3.73, 95% CI 1.59‐8.75) were associated with in‐breast pCR. Patients with invasive lobular carcinoma (ILC) were less likely to experience in‐breast pCR (OR 0.10, 95% CI 0.01‐0.73) than those with invasive ductal cancer. Axillary pCR was found in 65 clinically node‐positive patients (41%). Axillary pCR was more likely to occur in HR‐positive/HER2‐positive (OR 6.24, 95% CI 1.86‐20.90) and HR‐negative/HER2‐positive tumors (OR 6.41, 95% CI 1.95‐21.06), compared to HER2‐negative disease. In‐breast pCR was strongly associated with axillary pCR (OR 10.89, 95% CI 4.20‐28.22). Conclusion Response to NST in the breast and axilla is largely determined by receptor status, with high pCR rates occurring in HER2‐positive and triple‐negative tumors. For axillary pCR, in‐breast pCR and HER2‐positive disease are the most important predictive factors.