We studied the expression of an iC3b neoantigen (iC3b-NEO) in plasma from patients with systemic lupus erythematosus (SLE), by using a monoclonal antibody specific for iC3b/C3dg/C3d, to investigate the activation of the third component of complement in SLE. The plasma iC3b-NEO level in 40 untreated patients with active SLE was significantly higher than that in 36 normal subjects (mean +/- SD 31.5 +/- 13.9 micrograms/ml versus 12.3 +/- 3.3 micrograms/ml; P less than 0.001). The plasma iC3b-NEO level was highly correlated with clinical disease activity (tau = 0.62, P less than 0.0001), and it was the parameter most closely correlated with renal histologic activity in lupus nephritis (tau = 0.52, P less than 0.0001). Also, patients with diffuse proliferative lupus nephritis had the highest levels of plasma iC3b-NEO among all World Health Organization classes of lupus nephritis (P less than 0.01). We conclude that the plasma iC3b-NEO level is strongly associated with clinical disease activity and renal histologic activity in patients with SLE, and that plasma iC3b-NEO may be a sensitive and useful measure of complement activation in SLE.