Treatment of cancer patients with epidermal growth factor receptor (EGFR) inhibitors causes perifollicular inflammation in the skin. Mouse models with EGFR deficiency predicted this folliculitis and revealed that abrogation of EGFR disrupts hair follicle cycling. We hypothesized that the defect in progression through catagen resulting from EGFR deficiency causes cutaneous inflammation. EGFR regulation of the hair cycle and inflammation was investigated using skin-targeted deletion of Egfr (Krt14-Cre+/Egfrfl/fl mice). Hair cycle stage was assessed using histological criteria, analysis of follicular apoptosis and the position of the dermal papillae. Dorsal hair follicles of control mice synchronously entered catagen at 17 d and progressed to telogen by 21 d. In contrast, Egfr mutant follicles asynchronously entered catagen, with some follicles beginning catagen at 18 d or later, and others remaining in anagen through 24 d. Mast cells were examined because follicular mast cell precursors can facilitate the transition into catagen after their maturation and degranulation. Failed catagen progression preceded an inflammatory response in the mutant skin, which was characterized by a 40% or more increase in mast cell numbers beginning at 21 d. Mast cells in mutant skin were more likely to be degranulated as well. Neutrophils and macrophages increased in mutant skin by 28 d, subsequent to the increase in mast cell numbers. Transcriptional profiling was performed at 17 d, the time of normal catagen onset, using follicular RNA obtained from laser capture microdissection to identify EGFR-regulated mediators of the inflammatory response. In silico analyses of these data identified increased expression of 12 immune function genes in mutant hair follicles including the mast cell proteases Chymase and Tryptase. Additionally, the class I major histocompatibility (MHC) molecules H2-Q9, H2-Q7 and H2-D1 and class II MHC molecules H2-Eb1, H2-Dmb1 and H2-Dmb1/2 were over-expressed in mutant hair follicles consistent with a role for adaptive immunity in cutaneous inflammation following asynchronous catagen. Thus, an aberrant catagen transition and upregulation of pro-inflammatory genes preceded folliculitis in Egfr mutant skin. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1219. doi:1538-7445.AM2012-1219