Objective To determine the effect of imiquimod on psoriasis?like lesions in different strains of mice and the mechanism involved. Methods Two mouse strains, BALB/ c and C57BL/6, were chosen, onto the back of which 62. 5 mg of 5% imiquimod cream was applied. PAIS score was used to determine the morphological changes of mouse back skin. The histopathological changes of skin were observed by HE staining, the thickness of the epidermis was measured under a microscope, and the relative expression of cytokines related to the IL?23/ IL?17Axis was measured by real?time PCR. Results With the passage of time, psoriasis?like skin lesions gradually formed on the back skin of both BALB/ c and C57BL/6 mice. Compared with those in C57BL/6 mice, the PAIS score of BALB/ c mice was higher, and histopathological changes and epidermal thickening ( P < 0. 05 or P < 0. 01) were also more significant. Two days after the application of imiquimod, the relative expression of IL?23, IL?17A, and IL?17F mRNA in the two mouse groups all increased significantly, and both groups showed a dynamic change of an initial increase and then a decrease. The peak of expression in BALB/ c mice appeared 2 days after the application, and in C57BL/6 mice it appeared at 4 days. Conclusions Imiquimod can induce psoriasis?like lesions in both BALB/ c mice and C57BL/6 mice, but the lesions in BALB/ c mice appeared to be more typical, potentially making them more suitable for human psoriasis research. The activation of the IL?23/ IL?17Axis is one of the most important inducers of skin lesions.