Background: The prognostic significance of achieving an axillary pathologic complete response (AxpCR) following neoadjuvant chemotherapy (NAT) in clinically node-positive (cN+) breast cancer (BC) is well established; however, there is currently no consensus regarding the optimal strategy for axillary management, particularly in patients with HER2-positive BC. This study, which seeks to assess the utility of the maximum standardized uptake value of axillary lymph nodes (N-SUVmax) obtained from baseline 18F-FDG PET/CT scans, in conjunction with the absolute monocyte count (AMC), as predictors of AxpCR to NAT in patients with cN+ HER2-positive BC, promises to bring significant benefits to the field of breast cancer treatment. Methods: The clinical, pathological, and imaging data of HER2-positive BC patients with cN+, who were eligible for NAT at the time of diagnosis, were analyzed retrospectively. Individual receiver operating characteristic curves were employed to establish the optimal cut-off values for both baseline N-SUVmax and AMC. Results: Involving 117 patients diagnosed with HER2+BC, 86 initially presented with cN+ disease. Among this group, 56 patients, representing 66.3%, achieved AxpCR following NAT. Patients with an N-SUVmax of 3.5 or higher exhibited a 4.6-fold increased probability of achieving AxpCR (p=0.039, odds ratio [OR]=4.638 [1.081; 1.904]). Conversely, those with an AMC exceeding 340/mm³ experienced a 90.4% decrease in the likelihood of achieving AxpCR (p<0.001, OR=0.096 [0.028; 0.324]). The interaction between N-SUVmax and AMC was thoroughly investigated, revealing that an increase in AMC mitigated the significance of N-SUVmax on the probability of attaining AxpCR after treatment (p=0.006, OR=0.999 [0.997; 1.000]). Patients were categorized into three groups based on their N-SUVmax and AMC levels: 1. High N-SUVmax – Low AMC group (Group 1, n=38) 2. High N-SUVmax – High AMC group or Low N-SUVmax – Low AMC group (Group 2, n=37) 3. Low N-SUVmax – High AMC group (Group 3, n=11) Individuals in Group 2 (p<0.001; OR=0.047 [0.009; 0.237]) and those in Group 3 (p<0.001, OR=0.017 [0.002; 0.137]) demonstrated a significantly lower probability of achieving AxpCR following NAT compared to patients in Group 1. Conclusions: Evaluating axillary treatment response in the neoadjuvant setting presents a valuable opportunity for HER2-positive breast cancer patients. By combining baseline N-SUVmax and AMC, clinicians can enhance their ability to determine the most appropriate axillary surgical approach for each patient, paving the way for enhanced treatment outcomes.