OBJECTIVE Complement activation and ineffective clearance of complement-bearing immune complexes via erythrocytes contribute to the pathogenesis of systemic lupus erythematosus (SLE). Abnormally high levels of erythrocyte C4d and low levels of complement receptor 1 (CD35) have been reported in SLE and might have diagnostic utility. We investigated whether erythrocyte C4d and complement receptor 1 were specific for SLE and whether there was any association with disease activity. METHODS Expression of complement receptor 1 (CD35) and complement protein C4d on erythrocytes was measured by indirect immunofluorescence and flow cytometry on the same day as the blood draw, in patients with SLE, patients with rheumatic disease, and in normal controls. RESULTS Within the SLE population, there was no association with disease activity measured by the physician's global assessment or SELENA SLE Disease Activity Index, nor with past or current lupus nephritis. Assays were not specific for SLE, with higher levels also seen in antiphospholipid syndrome. CONCLUSIONS Overlap of erythrocyte C4d and CD35 between SLE and other rheumatic diseases limits their utility as diagnostic tests. However, longitudinal investigation of these assays is warranted, especially given the higher levels in some patients with primary antiphospholipid syndrome.