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 Tgfa ^wa1 or Egfr ^wa2 alleles. In this study, we show that Wa5 is a new allele of Egfr (Egfr ^Wa5 ) 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 Apc ^Min tumorigenesis, and levels of EGF-dependent EGFR phosphorylation demonstrates that Egfr ^Wa5 functions as an antimorphic allele, recapitulating many abnormalities associated with reduced EGFR activity. Furthermore, Egfr ^wa5 enhances Egfr ^Wa2 compound or Tgfa ^tm1Dcl double mutants exposing additional EGFR-dependent phenotypes. In vitro characterization shows that the antimorphic property of Egfr ^Wa5 is caused by a kinase-dead receptor acting as a dominant negative.