Abstract Introduction: We hypothesized that normal breast tissue in inflammatory breast cancer (IBC) patients contains intrinsic differences, including increased mammary stem cells and macrophage infiltration, which may promote the IBC phenotype. Materials and Methods: Normal breast tissue at least 5cm away from primary tumors were obtained from mastectomy specimens. This included an initial cohort of 8 IBC patients and 60 non-IBC patients followed by a validation cohort of 19 IBC patients and 25 non-IBC patients. Samples were immunostained for either CD44+CD49f+CD133/2+ stem cell markers or the CD68 macrophage marker and correlated with IBC status. Automated quantitation of positive cells was employed for the validation cohort. We also examined the association between IBC status and previously published tumorigenic stem cell and IBC tumor signatures in the validation cohort samples. Results: 8 of 8 IBC normal tissue samples expressed CD44+CD49f+CD133/2+ stem cell markers in the initial cohort as opposed to 0/60 non-IBC normal tissue samples (p=0.001). Similarly, the median number of CD44+CD49f+CD133/2+ cells was 25.7 in the IBC validation cohort as opposed to 14.2 in the non-IBC validation cohort (p=0.007). 7 of 8 IBC samples expressed CD68+ macrophages in initial cohort as opposed to 12/48 non-IBC samples (p=0.001). In the validation cohort the median number of CD68+ cells was 3.7 in the IBC cohort vs 1.0 in the non-IBC cohort (p=0.06). Normal tissue of IBC patients was positively associated with a tumorigenic stem cell signature (p=0.02) and with a 79-gene IBC gene signature (p<0.001). Conclusions: Normal tissue from IBC patients is enriched for both mammary stem cells and macrophages. Further, normal tissue of IBC patients has higher association with both a tumorigenic stem cell signature and IBC-specific tumor signature. Collectively, these data suggest that normal tissue from IBC patients is distinct from non-IBC normal tissue and may support the hypothesis that a primed normal breast contributes to the development of IBC symptoms upon oncogenic insult. Validation of these results in additional normal tissue in cancer-free women would better determine causality. Citation Format: Reddy JP, Atkinson RL, Larson RA, Burks JK, Smith D, Debeb BG, Ruffell B, Creighton C, Reuben JM, Krishnamurthy S, Symmans WF, Brewster A, Van Laere SJ. Stem cell and macrophage markers are enriched in normal tissue adjacent to inflammatory breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P4-03-14.