OBJECTIVE: To investigate the dose tolerance and potential clinical activity of a humanized antilymphocyte monoclonal antibody, CAMPATH-1H (C1H), in patients with active, refractory rheumatoid arthritis (RA). METHODS: Thirty adult patients with active, refractory RA were treated in an open-label, 3-center, dose-escalation study of subcutaneously injected C1H. Six patients were assigned to each of 5 dosage groups (0.3, 1.0, 3.0, 10.0 or 30.0 mg/day), and received 10 daily injections of C1H over a 12-day period. RESULTS: Side effects occurred primarily during the first 1-2 days of dosing, and included mild fever, chills, nausea, vomiting, headache, and, in a minority of patients, hypotension. All patients developed some discomfort at the injection site. Self-limited infections occurred in 5 patients during the 6-month study period. Peripheral blood lymphocyte counts fell promptly after initial dosing and recovered slowly, usually over 2-3 months. Serum antibodies to C1H developed in 54% of patients following treatment. Clinical improvement was observed in 56% of patients, based on the composite Paulus criteria, with a median time-to-response of 22 days and a median response duration of 32 days. CONCLUSION: C1H is a lymphocyte-depleting antibody that exhibits biologic potency when administered subcutaneously to patients with refractory RA. Its use is associated with mild to moderate toxicity and short-term amelioration of disease activity.