Objective. To investigate the safety, tolerability, pharmacokinetics, and immunologic activity of single intravenous infusions (0.2-10 mg/kg) of Orthoclone OKTcdr4a, a nondepleting humanized anti-CD4 monoclonal antibody (Mab) in patients with rheumatoid arthritis. Methods. Eighteen patients were treated with a single intravenous dose of Mab. Three patients each received 0.2, 0.5, 1.0, 2.0, 5.0, or 10.0 mg/kg of OKTcdr4a. Results. No patient had a significant change in CD4+ T cells in peripheral blood after treatment. No human antimurine antibodies were detected. At ≤ 1.0 mg/kg dose level, CD4 receptor saturation was ≤ 95% 24 h after infusion. At 5.0 mg/kg, CD4 receptor occupancy was a mean of 88% at 6 days after infusion. At 10 mg/kg, CD4 receptor occupancy was still a mean of 79% 2 weeks after infusion. No significant infusion related adverse events occurred. Two subjects had headaches at the time of drug administration. Two subjects were hospitalized for infections (pneumonia, Day 45; cellulitis, Day 14), which resolved with antibiotic therapy. Conclusion. OKTcdr4a was well tolerated at the doses used and saturation of CD4 receptors in peripheral blood could be routinely obtained for over one week with a single infusion of Mab.