Objective To observe the effect of long-term glucocorticoid (GC) administration on the metabolism and organs of normal rats. Methods Sixty clean-grade male KM rats ( body weight 32 ~ 35 g) were divided into four groups that were given topical urea ointment 1 g / d (control group), 0. 05% topical halometasone ointment 1 g / d ( topical halometasone group), 6 mg / ( kg·d) prednisone gavage ( prednisone group ), and 0.9 mg / ( kg·d ) subcutaneous dexamethasone (dexamethasone group), respectively, for 6 months. Metabolic variables ( including body weight, blood glucose and mean arterial pressure) were measured and evaluated at different times. After 6 months, the rats were euthanized and the pathological changes in the heart and liver tissues were evaluated. Results The metabolic variables of rats systemically treated with GC were significantly different compared with rats topically treated with GC; systemic GC administration caused accelerated weight gain, increased mean arterial pressure, increased fasting blood glucose concentration, and abnormal oral glucose tolerance, with the most significant changes seen in the prednisone group. Systemic GC administration caused obvious organ damage, comprising cell degeneration and fatty infiltration of heart tissue, and severe fatty infiltration, inflammatory infiltration, and lobular damage of liver tissue; the most serious organ damage was found in the dexamethasone group. Long-term topical GC administration had no significant effects on body weight, mean arterial pressure, fasting blood glucose concentration, and oral glucose tolerance, and did not cause organ damage in normal rats. Conclusions Long-term topical administration of halometasone ointment has less adverse effects and is safer than systemic administration of prednisone and dexamethasone. These findings provide important information regarding the clinical use of GC in patients.