Severe systemic lupus erythematosus affecting the kidney or central nervous system may lead to organ failure or death despite treatment with high doses of corticosteroids. To evaluate the clinical and immunologic effects of intravenous cyclophosphamide in this setting, we treated nine patients with monthly intravenous infusions of cyclophosphamide for six months. A comparison of characteristics at entry and follow-up revealed improvements (by paired t-test) in creatinine clearance (66 vs. 96 ml per minute, P less than 0.001); 24-hour urinary protein level (4.11 vs. 0.90 g, P less than 0.05), Farr anti-DNA titer (43 vs. 8.5 percent, P less than 0.01); complement components C3 (894 vs. 1150 mg per liter, P less than 0.05), C4 (154 vs. 222 mg per liter, P less than 0.05), and total complement activity (CH50) (88.7 vs. 113.4 IU, P less than 0.05); and Westergren erythrocyte sedimentation rate (60.2 vs. 34.4 mm per hour, P less than 0.0005). Other manifestations of lupus improved markedly in most cases, despite a reduction in the mean daily dose of prednisone, from 45 mg at entry to 17 mg at follow-up (P less than 0.01). The numbers of lymphocytes positive for T3, T4, T8, and B1 declined progressively during treatment. At follow-up, persistent decreases were observed in the T-lymphocyte subsets, whereas the absolute number of B lymphocytes had returned to levels near base line. T-cell proliferative responses at follow-up were not significantly different from entry values, except that the response to mitogenic anti-T11 (CD2) antibodies was decreased (P less than 0.01). Our data indicate that monthly intravenous administration of cyclophosphamide was associated with a substantial amelioration of severe systemic lupus, in conjunction with discrete changes in T-lymphocyte markers and T-cell function. This was a preliminary, uncontrolled study, but the results warrant further investigation of this form of treatment.