P-glycoprotein (P-gp) expels various drugs from cells, resulting in multidrug resistance, including against glucocorticoids. Here, we present a case of systemic lupus erythematosus (SLE) that suggests the importance of initial intensive treatment in overcoming unresponsiveness due to P-gp overexpression on activated lymphocytes. A 28-year-old woman had been diagnosed with highly active SLE including severe pericarditis, hemolytic anemia, lupus nephritis, and retinopathy. The disease activity of SLE progressed despite 1 mg/kg per day oral prednisolone. At the time, P-gp expression was extremely high, as evaluated by flow cytometric analysis on peripheral lymphocytes. After intensive treatment with three courses of methylprednisolone pulse therapy and plasmapheresis, we succeeded in controlling disease activity in association with marked reduction of P-gp overexpression; namely, the clinical symptoms immediately improved along with the reduction of P-gp expression. These results imply that patients with highly active SLE might have drug unresponsiveness that is mediated by P-gp overexpression on lymphocytes. Therefore, downregulation of P-gp by initial intensive immunosuppressive therapy might be important for overcoming glucocorticoid resistance. We also propose that measurement of P-gp on lymphocytes is a useful test for prediction of drug resistance and may assist in the selection of appropriate initial treatment.