The toxicity of Prednisolone farnesylate (PNF) gel, a synthetic glucocorticoid, was investigated in the Sprague-Dawley rat. PNF gel was administered dermally to the rats at doses of 0.125, 0.5 and 2.0 mg/kg/day for 52 weeks, then the drug was withdrawn for 8 weeks to evaluate the reversibility. The results are summarized as follows: 1. In the PNF gel 2.0 mg/kg/day group, thinning of the skin at the application site, slightly retarded body weight gains, a tendency toward a decrease in the white blood cell count, an elevation of serum GOT and GPT activity, free fatty acid level, and a decrease in alpha 1-globulin fraction were observed. In the pathological examinations, decreased organ weights of the thymus, spleen and adrenal glands, and thinning of the skin were observed. Histopathological examination revealed atrophy of the thymus and zona fasciculata of the adrenal glands, thinning of the skin with atrophied skin appendages, and hepatocellular hypertrophy with hypertrophied uncleus in the perilobular zone. 2. In the PNF gel 0.5 mg/kg/day group, thinning of the skin at the application site and a decrease in alpha 1-globulin fraction were observed. Histopathologically, thinning of the skin atrophied skin appendages was observed. 3. In the PNF gel 0.125 mg/kg/day group, there were no toxic signs induced by the drug. 4. After the 8-week recovery period, the changes in the skin were observed in the 2.0 mg/kg/day group, but the severity was lowered. The other changes disappeared and so it was demonstrated that the changes were reversible. 5. Based on these results, it was concluded that the overt toxic dose of PNF gel was 0.5 mg/kg/day and the non-toxic dose was 0.125 mg/kg/day in the present study.