Background: IBC is an aggressive form of breast cancer with poor prognosis. Combined multimodality Rx results in 5 year median OS of 30-50%, underscoring the unmet need for novel targeted strategies. Our preclinical research in cell lines and xenografts suggests a role for activated PI3K/AKT/mTOR pathway in IBC. IBC cells not only express high levels of IL-6 and IL-8 but can recruit tumor activated macrophages (TAMs), which can further induce IL-6, IL-8 and activate JAK2/STAT3 pathway. We therefore investigated independent and combined activity of these pathways. Methods: Archived tissue specimens of 42 IBC pts (1999 - 2009) and 13 controls (normal breast) were analyzed using IHC and scored by 3 independent pathologists. Results were defined as: 0, 1+ = neg; 2+ = pos for activated mTOR (phosphorylatedS6) and 0 = neg; 1+, 2+ = pos for activated nuclear JAK2/STAT3 (pJAK2; pSTAT3), cytokine (IL-6), macrophage infiltration (CD68) and TAMs (CD163). Proportion of IBC cases with pos expression were compared to proportion among controls (Fishers exact test). Clinical and survival data were obtained. Results: Median age at diagnosis - 44.5 yrs (29-64). 22 had HER2 overexpression (8 also ER+) and 9 were ER-/HER2-; ER & HER2 unknown for 1 and 2 pts respectively. Majority were Rxed with neoadjuvant anthracycline and/taxane without adjuvant trastuzumab. There were 24 deaths. Median OS: 67 mths (95% CI: lower 41). Proportions of IBC cases with pos expression when compared to controls are listed in the table (Fishers p value: <0.0001). Of the 31 pts with complete biomarker data who were PS6 pos, 97% had activated JAK2 & 58% had activated STAT3 (McNemar’s chi square, p <0.001). 24/31 (80%) showed strong infiltration of macrophages and TAMs. All cases had widespread IL6 staining. Conclusions: This study validates our preclinical findings and shows hyperactivation of mTOR and JAK2 signaling in vast majority of IBC specimens, with close association between mTOR, TAMs, cytokines and JAK2/STAT3 pathways. These findings support a role for dual blockade of mTOR and JAK/STAT pathways in clinical trials.