Itgb2tm1Bay PL/J mice express low levels of the β2 integrins and, unlike Itgb2tm1Bay C57BL/6J mice, spontaneously develop psoriasiform dermatitis with several similarities to human psoriasis. To define the genetic requirements for skin disease susceptibility we analyzed more than 500 F2 progeny from an Itgb2tm1Bay (PL/J x C57BL/6J) intercross. We found that 23.5% developed chronic inflammatory skin disease, although significant differences in severity were observed. Another CD18 mutation, Itgb2tm2Bay has now been generated that completely eliminates CD18 expression. Surprisingly, of 10 Itgb2tm2Bay homozygote PL/J N4 mice generated, none showed clinical or histopathological evidence of disease. However, Itgb2tm1Bay/Itgb2tm2Bay PL/J mice developed dermatitis indistinguishable from Itgb2tm1Bay PL/J mice. In addition, approximately half of Itgb2tm1Bay/Itgb2tm2Bay (C57BL/6J x PL/J)F1 mice were found to develop mild psoriasiform dermatitis identical to the early stages of disease seen in Itgb2tm1Bay PL/J mice. Collectively, these results suggest a complex inheritance pattern of psoriasiform dermatitis in this model that involves lowered, but not absent, CD18 expression and at least two additional PL/J loci for the development of severe disease. The susceptibility allele can act in either a heterozygous or homozygous state, dependent on the level of CD18 expression.