To investigate the safety and pharmacology of a humanized monoclonal antibody against CD40-ligand (IDEC-131) in patients with systemic lupus erythematosus (SLE). Cohorts of 3 to 5 patients with symptomatic lupus each received 0.05, 0.25, 1.0, 5.0, or 15.0 mg/kg of IDEC-131 as a single intravenous infusion. Patients were followed for 3 months to evaluate toxicity and pharmacokinetics. This phase I, single dose, dose-escalating study was conducted in 23 patients at a single institution. All patients experienced at least 1 adverse event (AE) during a 3 month followup period, although 58 AE in 17 patients were considered possibly or probably related or of unknown relationship to treatment. No dose relationship in the distribution of AE was apparent. No infusion related cytokine-release syndrome was observed; no infusions were interrupted, and all patients completed treatment. Eight mild (grade 1 or 2) infections were reported in 8 patients. All infections were considered unrelated to drug administration and all resolved uneventfully. No patient developed detectable antibodies to IDEC-131. Flow cytometry revealed no apparent treatment related depletion of lymphocyte subsets. Pharmacokinetic analysis indicated that the maximum serum concentration and the area under the concentration curve of IDEC-131 were proportional to the dose administered. At doses between 1.0 and 15.0 mg/kg, the serum half-life ranged from 299 to 320 h. Efficacy was not formally evaluated in this single dose study. IDEC-131 (humanized Mab against CD40L) administered in a single intravenous infusion at doses of 0.05-15.0 mg/kg is safe and well tolerated in patients with SLE.