Diffuse proliferative lupus nephritis (DPLN) is a serious organ complication. Drug resistance correlates with P-glycoprotein (P-gp) expression on activated lymphocytes. We encountered a refractory DPLN patient with expansion of peripheral CD69/CXCR3-co-expressing P-gp+CD4+ cells producing IL-2 and IL-6. Treatment with high-dose corticosteroid combined with biweekly intravenous cyclophosphamide pulse therapy (IVCY) failed to reduce the population of activated P-gp+CD4+ cells or control the disease activity. Methotrexate (MTX) with monthly IVCY reduced activated P-gp+CD4+ cells and improved the clinical symptoms, resulting in long-term remission and tapering of corticosteroids. MTX-IVCY combination therapy, which down-regulates the activated P-gp+CD4+ cell-mediated disease activity, may be useful for the treatment of refractory DPLN.