Imiquimod (IMQ) produces a cutaneous phenotype in mice frequently studied as an acute model of human psoriasis. Whether this phenotype depends on strain or sex has never been systematically investigated on a large scale, although such effects could impact efforts to translate research findings. This study used RNA-seq to evaluate the psoriasiform phenotype elicited by 5 days of Aldara (5% IMQ) treatment in both sexes of 7 mouse strains (C57BL/6J (B6), BALB/cJ, CD1, DBA/1J, FVB/NJ, 129X1/SvJ and MOLF/EiJ). The response of MOLF males was aberrant, with decreased expression of differentiation-associated genes (elevated in other strains). Key aspects of the IMQ response differed between the two most commonly studied strains (BALB/c and B6). Compared with BALB/c, the B6 phenotype showed increased expression of genes associated with DNA replication, IL-17A stimulation and activated CD8+ T cells, but decreased expression of genes associated with interferon signaling and CD4+ T cells. Although IMQ-induced expression shifts mirrored psoriasis, responses in BALB/c, 129/SvJ, DBA, MOLF mice were more consistent with other human skin conditions (e.g., wounds or infections). IMQ responses in B6 mice were most consistent with human psoriasis. These findings demonstrate strain-dependent aspects of IMQ dermatitis in mice, and show that IMQ does not uniquely model psoriasis but in fact triggers a core set of pathways active in diverse skin diseases. Nonetheless, IMQ dermatitis in B6 mice was most similar to human psoriasis, suggesting that B6 may be better than other strains for the purpose of modeling psoriasis disease mechanisms.