Objective: To establish a mouse model of psoriasis complicated by bone loss by long-term topical application of imiquimod. Methods: Twelve 10-week-old Kunming mice were randomly and equally divided into 2 groups: experimental group topically treated with 50 mg/d imiquimod cream every day on the shaved back, and control group topically treated with equivalent vaseline ointment every day on the shaved back. Skin manifestations were observed on the mouse back every day. The mice were sacrificed 10 weeks later. Before the sacrifice, the degree of erythema, scaling and skin thickening was evaluated, psoriasis area severity index (PASI) was calculated, mouse weight was measured, and eyeball blood was obtained. After the sacrifice, skin lesions on the back were resected and subjected to hematoxylin-eosin staining, so as to evaluate histological changes. Then, the left tibia was obtained from the mice, immunohistochemical staining was performed to observe the expression and distribution of osteoprotegerin (OPG) and receptor activator of nuclear factor kappa-β ligand (RANKL) in bone tissues, and micro-computerized tomography was conducted to determine the bone mass of spongy bone, and the bone volume-to-total volume ratio, number, thickness, spacing and connectivity density of the trabecular bone in the proximal tibia. The left femur was also obtained from the mice, and subjected to three-point bending test for evaluating its biomechanical properties. Enzyme-linked immunosorbent assay (ELISA) was performed to detect serum levels of tumor necrosis factor (TNF) -α and interleukin (IL) -17. RNA was extracted from the right tibia, and real-time PCR was conducted to determine the mRNA expression of OPG and RANKL. Two-independent-sample t test was used to compare the above indices between two groups. Results: Ten-week topical stimulation with imiquimod could lead to psoriasiform dermatitis on the mouse back, presenting as erythema, scales and skin thickening. The PASI score was significantly higher in the experimental group (9.167 ± 1.722) than in the control group (0, t = 13.31, P < 0.001) . Hematoxylin-eosin staining showed thickened spinous layer, extended rete ridges, infiltration of inflammatory cells in the superficial dermis, spongiosis, vasodilatation and increased hair follicles in the experimental group. Immunohistochemical staining revealed that the expression of OPG and RANKL was significantly higher in the experimental group (16 021.33 ± 1 954.61, 35 433.33 ± 1 197.95 respectively) than in the control group (3 307.00 ± 1 158.72, 13 644.67 ± 4 764.61, respectively; t = 9.692, 7.682 respectively, both P < 0.01) . Micro-computerized tomography showed that the bone volume-to-total volume ratio and thickness of trabecular bone in the proximal tibia were significantly lower in the experimental group than in the control group, but the spacing of trabecular bone was significantly higher in the experimental group than in the control group (P < 0.01 or < 0.05) . There were no significant differences in the elastic modulus and fracture energy of the femur between the experimental group and control group (both P > 0.05) . Moreover, no significant differences in the serum levels of TNF-α and IL-17 were observed between the two groups (both P > 0.05) . Real-time PCR revealed that the mRNA expression of OPG and RNAKL was significantly higher in the experimental group than in the control group (P < 0.05, < 0.01 respectively) . Conclusions Long-term topical application of imiquimod can not only induce psoriasiform dermatitis in mice, but also lead to bone loss of spongy bone and micro-architectural deterioration in the proximal tibia. Thus, mouse models of psoriasis complicated by bone loss can be established by long-term imiquimod stimulation.