Background: The epidermal growth factor receptor (EGFR) network is essential for proper development and homeostasis of skin and hair. However, detailed dissection of the role of the EGFR in hair follicle development and cycling have been impaired by the early mortality of EGFR knockout mice. Objectives: We have studied in Waved-5 mice carrying an antimorphic EGFR allele (Egfrwa5), whose product acts as a dominant-negative receptor, whether strongly reduced EGFR signaling impacts on the hair and skin phenotype. Methods: Histomorphometry and immunohistochemistry were employed to study hair follicle morphogenesis stages and cycle induction in Waved-5 mice and control littermates during embryonic development and postnatal life. Results: By routine histology and quantitative histomorphometry, no significant abnormalities in the epidermis and in hair follicle morphogenesis were detected, while the initiation of hair follicle cycling was slightly, but significantly retarded. Proliferation and apoptosis of epidermal and hair matrix keratinocytes of Waved-5 mice appeared unaltered. Intriguingly, the thickness of the subcutis and the percentage of proliferating subcutaneous adipocytes were significantly reduced in Waved-5 mice around days P8.5 to P10.5. Although no differences in total body weight gain could be detected, Wa5 mice showed a significant reduction in the percentage of body fat at P8.5. Conclusion: Our results suggest the presence of effective compensatory mechanisms in murine skin in vivo that ensure nearly normal epidermal and hair follicle keratinocyte function despite very low levels of EGFR-mediated signaling. Our unexpected findings of transiently reduced subcutaneous adipose tissue indicate a role for the EGFR in regulating subcutaneous fat. © 2009 Japanese Society for Investigative Dermatology.