Background: The immune system reveals to play a pivotal role in HER2 positive breast cancer responsiveness to trastuzumab therapy. The platelet-lymphocyte ratio (PLR) is representative blood markers of systemic inflammatory responses. It is suggested as an immunity biomarker in gastric, lung cancer and other cancers, but is less well known in breast cancer. The aim of this study is to investigate the predictive role of PLR in HER2 positive metastatic breast cancer patients treated with first-line trastuzumab therapy. Methods: This study retrospectively includes 287 HER2 positive metastatic breast cancer patients with first-line trastuzumab therapy in Cancer Hospital of the University of Chinese Academy of Science from January 2010 to November 2021. The Peripheral blood cell count of these patients before trastuzumab treatment is evaluated to calculate PLR. All patients are separated into PLR^high or PLR^low cohort according to cut-off value defined as median value. Median value of PLR is 154.5, more than 154.5 is defined by PLR^high, otherwise defined as PLR^low. Kaplan–Meier curves is performed to assess progression-free survival (PFS). Univariate and multivariate analyses were performed using a logistic regression model. Results: Of 287 patients, 228 patients’ peripheral blood cell count were available. 114 patients are PLR^high and 114 patients are PLR^low. Patients with PLR^high achieved a significantly worse PFS compared to those with PLR^low (median PFS: 8.47 months vs.9.92 months, HR:1.475, 95% CI:1.068-2.038, P = 0.014). Besides, mean corpuscular volume (< 89.2fL), lymphocyte (< 1.3), mean hemoglobin (< 30PG) are also related to worse PFS (P= 0.003,0.033,0.055,respectively). Importantly, PLR^high, mean corpuscular volume, remain independent predictors in the multivariate COX analysis (HR 0.689,95%CI 0.493-0.962, P = 0.028;HR1.646,95%CI 1.177-2.302, P = 0.004). Conclusions: Patients with pre-treatment PLR^high showed less sensitivity to trastuzumab therapy for metastatic breast cancer patients independent of other molecular characteristics. The pre-treatment PLR levels might serve as a predictive biomarker for HER2 positive breast cancer with trastuzumab therapy.