Female NZB/W mice develop a disease closely resembling human systemic lupus and serve as an animal model for therapeutic studies. Several previous studies have demonstrated the efficacy of different immunosuppressive drug regimens in the therapy of glomerulonephritis in NZB/W mice. After the onset of immune complex deposition, treatment with intermittent high doses of cyclophosphamide or daily low doses of the combination of cyclophosphamide, azathioprine, and methylprednisolone has been effective. The present study was designed to compare such effective regimens in mice early in the course of their renal disease versus mice late in the course of glomerulonephritis. One to three injections of high-dose cyclophosphamide during active immune complex deposition and early histologic changes were significantly effective in prolonging survival, whereas treatment late in the course of glomerulonephritis was less effective. Even more striking was the result of low-dose combination therapy. Daily treatment with cyclophosphamide, azathiprine, and methylprednisolone (C + A + M) effectively prolonged survival when started in mice 5 months old, but was of no benefit when started in those 8 months of age. In a concluding experiment, older mice were selected on the basis of degree of renal disease and studied with regard to proteinuria and survival. Those with mild renal disease responded to daily treatment for 6 months with C + A + M at 1 mg/kg of each drug, whereas those with advanced renal disease at the onset of therapy did not benefit.