Trastuzumab emtansine (T-DM1) is a mainstay therapy for HER2-positive metastatic breast cancer (mBC). However, identifying patients who will benefit most remains a challenge due to the lack of reliable biomarkers. The recently developed pan-immune-inflammation value (PIV), a novel immune-inflammation marker, could aid in this regard, considering the immunomodulatory effects of T-DM1. Therefore, we aimed to evaluate the association between the PIV and the efficacy of T-DM1 in patients with HER2-positive mBC. A total of 122 HER2-positive mBC patients treated with T-DM1 were included. Receiver operating characteristic (ROC) curve analyses were conducted to determine the optimal PIV threshold value for survival prediction. Kaplan-Meier survival curves and Cox regression analyses were used for univariable and multivariable survival analyses, respectively. The median age was 51 years, and 95.1% of the patients had ECOG PS 0-1. The optimal PIV cutoff value was identified as 338 in ROC analyses (AUC: 0.667, 95% CI: 0.569-0.765, p = 0.002). The multivariate analysis revealed that patients in the high-PIV group had significantly shorter OS (HR: 2.332; 95% CI: 1.408-3.861; p = 0.001) and PFS (HR: 2.423; 95% CI: 1.585-3.702; p < 0.001) than patients in the low-PIV group. Additionally, both ORR and DCR were significantly lower in the high-PIV group (36.6% vs. 61.3%, p = 0.011; 56.1% vs. 76.0%, p = 0.027). Our findings suggest that pre-treatment PIV may be a novel prognostic biomarker for HER2-positive mBC patients receiving T-DM1. A low PIV level is associated with more favorable outcomes. Future prospective studies are warranted to validate these findings and explore the potential utility of PIV in aiding treatment decisions.