Mice heterozygous for the N-ethyl-N-nitrosourea- induced Waved-5 (Wa5) mutation, isolated in a screen for dominant, visible mutations, exhibit a wavy coat similar to mice homozygous for the recessive Tgfawa1 or Egfrwa2 alleles. In this study, we show that Wa5 is a new allele of Egfr (EgfrWa5) containing a missense mutation within the coding region for the highly conserved DFG motif of the tyrosine kinase domain. In vivo analysis of placental development, modification of ApcMin tumorigenesis, and levels of EGF-dependent EGFR phosphorylation demonstrates that EgfrWa5 functions as an antimorphic allele, recapitulating many abnormalities associated with reduced EGFR activity. Furthermore, Egfr wa5 enhances EgfrWa2 compound or Tgfatm1Dcl double mutants exposing additional EGFR-dependent phenotypes. In vitro characterization shows that the antimorphic property of EgfrWa5 is caused by a kinase-dead receptor acting as a dominant negative.