Itgb2tm1BayPL/J mice express low levels of the β2integrins and, unlike Itgb2tm1BayC57BL/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, Itgb2tm2Bayhas now been generated that completely eliminates CD18 expression. Surprisingly, of 10 Itgb2tm2Bayhomozygote PL/J N4 mice generated, none showed clinical or histopathological evidence of disease. However, Itgb2tm1Bay/Itgb2tm2BayPL/J mice developed dermatitis indistinguishable from Itgb2tm1BayPL/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 Itgb2tm1BayPL/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.