There is a close relationship between inflammatory cells and tumors, but the pathways that connect the two remain unclear. This research explores the clinical and prognostic value of the systemic inflammation response index (SIRI) in breast cancer patients. The study included 477 breast cancer patients who underwent neoadjuvant chemotherapy and 308 breast cancer patients who did not in our center between January 1998 and December 2016. Optimal SIRI threshold values were determined using the receiver operating characteristic curve (ROC). Patients were then reclassified as SIRI ≥0.80 group (High SIRI group) and SIRI <0.80 group (Low SIRI group). The outcomes were analyzed by statistical methods. The univariate and multivariate analyses demonstrated that SIRI independently predicted survival in breast cancer. The disease-free survival (DFS) and overall survival (OS) in patients with low SIRI scores were significantly longer in contrast to those with high SIRI scores (41.50 vs. 37.63 months, and 64.57 vs. 58.42 months). Further subgroup analyses revealed that low SIRI score patients who also had either early breast cancer, advanced breast cancer, or different molecular subtypes also possessed longer mean survival time of DFS and OS in contrast to those with high SIRI levels (χ2 = 2.379, p = 0.123, and χ2 = 5.153, p = 0.023; χ2 = 11.080, p = 0.0009 and χ2 = 15.900, p < 0.0001; χ2 = 16.020, p < 0.0001 and χ2 = 22.050, p < 0.0001, respectively). SIRI serves as an easily accessible, replicable, and minimally invasive prognostic tool in breast cancer patients. Lower SIRI scores were predictive of a longer DFS and OS after surgery in breast cancer patients. SIRI may serve as a marker to guide clinical management and prognostication of breast cancer.Copyright © 2022 Zhu, Chen, Kong, Wang, Fang, Li and Wang.