Abstract： Objective To study the protective effects of rosiglitazone against early skin changes in experimental diabetic rats. Methods Diabetic models were established in male Wistar rats aged 8 to 10 weeks by using streptozotocin (STZ). Then, 39 experimental diabetic rats were equally divided into insulin-treated diabetic group (DI group), rosiglitazone-treated diabetic group (DR group), diabetic control group (DC group),and 13 normal rats served as the control (C group). The rats were given subcutaneous insulin (1 - 2 U) twice daily in DI group, intragastric rosiglitazone (5 mg/kg) once daily in DR group, and intragastric sterile water in DC and C groups. Sixteen weeks later, heart blood samples were collected from all the rats for the measurement of tumor necrosis factor (TNF)-α, interleukin (IL)-6, C reactive protein (CRP), superoxide dismutase (SOD) and P substance (SP) levels, then the rats were killed and tissue samples were obtained from the medial area of the dorsal skin and subjected to pathological observation, measurements of skin as well as dermal thickness, and immunohistochemical examinations for the expression of advanced glycation end products(AGEs) and peroxisome proliferator activated receptor-γ (PPAR-γ). Results The levels of IL-6, TNF-α and CRP in the DC group were significantly higher than those in the C group (135.05 ± 43.39 ng/L vs. 99.92 ±32.36 ng/L, 1.45 ± 0.67 μg/L vs. 0.86 ± 0.60 pg/L, 3.51 ± 0.62 mg/L vs. 2.54 ± 1.31 mg/L, all P < 0.05),while no significant difference was found between C group and DI group or DR group (all P> 0.05). Decreased levels of SOD and SP were noted in the DC group (70.71 ± 37.52 U/ml, 22.22 ± 7.93 ng/L), compared withthe C group (137.76 ± 27.6 U/mL, 29.57 ± 3.74 ng/L, both P< 0.01), DI group (149.96 ± 13.25 U/mL, P<0.01; 29.79 ± 5.21 ng/L, P< 0.05) and DR group (128.50 ± 38.27 U/mL, P< 0.01; 33.35 ± 15.0 ng/L, P<0.05 ). Micrometer measurements indicated that the skin thickness was significantly lower in the DC group than in the C group, DI group and DR group (0.77 ± 0.18 mm vs. 1.59 ± 0.26 mm, 1.47 ± 0.50 mm and 1.22 ±0.47 mm, P < 0.01, 0.01, 0.05 respectively). Histological observation found a mild disarrangement of epidermal cells, shrinkage, swelling and degeneration of dermal collagen as well as progressive atrophy or disappearance of subcutaneous fat in the DC group. No obvious histological changes appeared in the DI or DR group. Immunohistochemistry indicated that AGEs and PPAR-γ proteins, which were stained into brown granules, were located in the vascular basement membrane, stromal cells, etc, of skin. The DC group showed the highest expression of AGEs but lowest expression of PPAR-γ. Conclusions There is an accumulation of AGEs and elevated expressions of inflammatory factors in the skin of experimental diabetic rats, and rosigLItazone shows a protective effect against the early skin changes.