Abstract Background: Inflammatory breast cancer (IBC) is an extremely aggressive form of locally advanced breast cancer that affects approximately 5% of breast cancer patients. The prognosis of IBC patients is remarkably poor, with a three-year survival rate of approximately 30% compared to 60% for non-IBC breast cancer patients. The etiology of IBC is largely unknown. A few risk factors have been reported such as body mass index (BMI) and educational level. Prior evidence has also implicated genetic components in IBC etiology. For instance, the reported familial cases and racial incidence disparity of IBC patients, as well as the fact IBC patients typically have a younger age onset than non-IBC patients, all indicated the possible involvement of genetic factors. Nevertheless, as yet no genetic epidemiological study has been reported to evaluate IBC genetic predisposition. Methods: To test the hypothesis that genetic variants and mutations may affect IBC susceptibility, we performed whole exome sequencing in a pilot case-control study that contained 70 IBC cases and 119 unrelated cancer-free controls. Sequencing data were de-multiplexed, filtered, assessed for various quality control metrics, mapped to reference genome and annotated. Comprehensive single variant-based, gene-centered, and pathway-based analyses were conducted to identify variants, genes, and pathways that may be involved in IBC predisposition. Results: We obtained > 50x on-target sequencing coverage of the whole exome in > 90% of the patients. In single variant analysis, we identified six variants reaching genome-wide significance. Four variants were encoded by genes that have been implicated in breast cancer development including MALAT1, MAP3K9, POLR3B, and FIP1L1. Two variants were encoded by novel genes that have not been related to breast cancer, including CCDC30 and LINC01565. Two types of analyses based on a gene-centered strategy identified top genes such as SLC39A4, CDHR1, AP5Z1, GNB3, ITGA10, etc. However, possibly due to the limited sample size, none of these genes reached genome-wide significance. Ingenuity Pathway Analysis (IPA), using the complete list of significant genes identified by each of these analyses all reported "cancer" as the highest possible disorder associated with these genes, demonstrating the biological plausibility of our findings. Moreover, canonical pathways such as IL4 signaling, glycogen degradation, epithelial adherence junction signaling, and CCR3 signaling in eosinophils were among the top pathways that were found involved in IBC predisposition. Conclusion: Overall, we provided novel preliminary evidence that genetic variants are potentially associated with the risk of developing IBC. We are currently conducting validation studies with larger sample sizes are warranted to confirm these findings and identify additional genetic susceptibility loci. Citation Format: Ye Z, Li B, Wang C, Zhong X, Wei Q, Mu Z, Austin L, Jaslow R, Avery T, Palazzo J, Biederman L, Yang H, Cristofanilli M, IBC Inflammatory Breast Cancer International Consortium. Novel genetic susceptibility loci for inflammatory breast cancer identified by whole exome sequencing. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P6-18-01.