Inflammation has been linked with cancer, but whether it is part of the problem or part of the solution remains to be a matter of debate in breast cancer. Our group and others have demonstrated that inflammation aggravates cancer progression, however, some claim that inflammation may support immune cell infiltration and suppress cancer. We defined the gene set variation analysis of the Molecular Signatures Database Hallmark inflammatory response gene set as the inflammatory pathway score and analyzed 3632 tumors in total from 4 breast cancer cohorts (METABRIC, TCGA, GSE25066, and GSE21094). In the whole breast cancer cohort, high score tumors were associated with aggressive clinical characteristics, such as worse disease specific survival (p = 0.002), higher Nottingham histological grade (p < 0.001), as well as younger age (young < 65 yo, 65 yo < as elderly; p < 0.001). SphK1 high expression were associated with higher inflammatory score with the striking consistency in the two cohorts (both p < 0.001). Furthermore, inflammatory score was significantly elevated in tumors that express high levels of S1P receptor 1 (S1PR1) (both p < 0.001), and sphingosine kinase 2 (SphK2) low expression tumors were also associated with higher inflammatory score (both p < 0.001). Inflammatory score was significantly higher in Triple Negative (TNBC) (p < 0.001) as well as Basal and Normal subtypes (p < 0.001) compared with the other subtypes in both METABRIC and the TCGA cohorts, which suggest that the detrimental effect of high level of inflammation may be because it includes a more aggressive subtype. On the contrary, high score within TNBC was significantly associated with better survival (DSS; p = 0.014, OS; p = 0.015). TNBC with high score enriched not only IFN-α, IFN-γ response, IL-2/STAT5 signaling, Allograft rejection, Complement, p53 pathway, Reactive Oxygen, and Apoptosis, but also TNF-α signaling, IL6-JAK-STAT signaling, TGF-β signaling, Coagulation, Angiogenesis, EMT, KRAS signaling, and PI3K-AKT-MTOR signaling gene sets (all FDR < 0.25 in both cohorts). High score was associated with mainly favorable anti-cancerous immune cell infiltration, including CD8 T cell, CD4 memory T cell, M1 Macrophage, and dendritic cell (all p < 0.001 in both cohorts), as well as Leukocyte fraction (p < 0.001), TIL regional fraction (p = 0.027), Lymphocyte infiltration (p < 0.001), IFN-γ response (p < 0.001) and TGF-β response (p < 0.001) and cytolytic activity scores (p < 0.001 in both cohorts). Although the inflammatory pathway score was not associated with neoadjuvant treatment response, it associated with expressions of immune checkpoint molecules (all p < 0.001 in both cohorts). In conclusion, inflammation was associated with worse outcome in the whole breast cancer cohort, but with better outcome in TNBC, which was associated with favorable anti-cancerous immune response and immune cell infiltrations. Citation Format: Masanori Oshi, Newman Stephanie, Yoshihisa Tokumaru, Ryusei Matsuyama, Itaru Endo, Kazuaki Takabe. Is inflammation a hero or a villain in human breast cancer? [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS18-33.