OBJECTIVE To determine whether opsonization of Streptococcus pneumoniae with C3b/iC3b is impaired in serum from patients with SLE. METHODS The ability of serum samples from 30 patients with SLE, 20 with non-SLE rheumatic diseases (RA, PsA, AS, SS) and 20 healthy controls to opsonize S. pneumoniae (strains D39 and Io11697) with C3b/iC3b was assessed using a standardized FACS technique and a FACSCalibur flow cytometer. Results were compared among the three groups using analysis of variance, followed by pairwise comparisons among groups using the Mann-Whitney U-test. RESULTS The proportion of bacteria positive for C3b/iC3b was significantly lower in serum from patients with SLE (strain D39: 60.3% +/- s.e.m. 2.87, strain Io11697: 55.3% +/- 3.8) compared with healthy controls (strain D39: 70.6% +/- 2.0, P = 0.01; strain Io11697: 67.8% +/- 2.6; P = 0.05) and non-SLE rheumatic controls (strain D39: 69.8% +/- 3.1; P = 0.03). For the patients with SLE, there was no association between C3b/iC3b deposition and serum complement levels or measurable classical pathway activity. C3b/iC3b deposition on S. pneumoniae was significantly lower in serum from SLE patients with a past history of pneumonia (n = 3) compared with those without (n = 27; P = 0.03). CONCLUSIONS Opsonization of S. pneumoniae with C3b/iC3b was significantly reduced in serum from patients with SLE compared with non-SLE rheumatic disease and healthy controls. Failure to appropriately activate the immune system via complement may contribute to the increased susceptibility of SLE subjects to infections, and may correlate with a risk of pneumonia in a subgroup of SLE patients.