Atacicept, a recombinant fusion protein containing the extracellular, ligand-binding portion of the transmembrane activator and calcium modulator and cyclophilin-ligand interactor receptor, and the Fc portion of human immunoglobulin (Ig) G, is designed to block the activity of B-lymphocyte stimulator and a proliferation-inducing ligand, and may have utility as a treatment for B-cell-mediated diseases, such as systemic lupus erythematosus (SLE). This Phase Ib study investigated the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics of intravenous (i.v.) atacicept in patients with mild-to-moderate SLE. Patients (n = 24) were randomised (5:1) to receive atacicept (single dose: 3, 9 or 18 mg/kg; or multiple dose: 2 x 9 mg/kg) or matching placebo. Patients were followed for 6 weeks after dosing (9 weeks in the 2 x 9 mg/kg cohort). Local tolerability of atacicept was comparable with that of placebo, with only mild injection-site reactions reported with atacicept. Atacicept i.v. was generally well tolerated, both systemically and locally, in patients with mild-to-moderate SLE. Atacicept displayed non-linear PK, which was predictable across doses and between single and repeat doses. The biological activity of atacicept was demonstrated by its marked effect in reducing B-cells and Ig levels in patients with SLE. This supports the utility of this therapeutic approach in the treatment of autoimmune diseases, such as SLE.