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Systemic lupus erythematosus (SLE) is a systemic autoimmune disease with polymorphic clinical manifestations that range from mild symptoms to life-threatening multiorgan dysfunction. The combination of heterogeneous clinical presentations at the time of diagnosis and unpredictable disease courses represents an immense medical and scientific challenge to biomarker development. Despite our advancing knowledge of the pathogenesis of SLE, few lupus biomarkers have been validated and widely accepted, and those in routine clinical use have been in place for decades (1,2). The dearth of lupus biomarkers is a major contributing factor to challenges in the clinical care of patients with lupus, in the accurate and thorough interpretation of clinical lupus research, in randomized controlled clinical trials, and in the development of new therapeutic agents for lupus. The US Food and Drug Administration has not approved a new drug for lupus in >50 years. In lieu of more useful lupus biomarkers, numerous indices have been developed in an attempt to measure disease activity in patients with lupus; the most widely used indices are the Systemic Lupus Activity Measure (SLAM) (3), the Safety of Estrogens in Lupus Erythematosus: National Assessment (SELENA) version of the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) (4), and the British Isles Lupus Assessment Group index (5). All of these indices have been validated and have excellent reliability, validity, and responsiveness to change. However, these indices are used almost exclusively by lupus research specialists; intense training is required to accurately complete these indices, and they may be too complex, cumbersome, and time-consuming to be used in routine clinical practice. Numerous studies have documented abnormalities in complement activation and clearance of immune complexes by erythrocytes as central pathogenic mechanisms in SLE (6,7). Measurement of serum C3 and serum C4 has traditionally been the gold standard for monitoring disease activity in patients with SLE; however, several major weaknesses in this approach have been previously identified. First, there is a wide range of variation of serum C3 and serum C4 levels among healthy individuals, and this range overlaps with the range observed in patients with SLE. Second, these are measurements of precursors rather than products of complement activation. Systemic inflammation resulting in an acute-phase response can increase synthesis of C3 and C4 that balances the increased catabolism of these proteins. Third, hereditary deficiencies and partial deficiencies of C4-null alleles may result in persistently lower-than-normal serum C4 levels because of decreased synthesis rather than because of increased complement activation and/or active SLE. Although the value of using serum C3 and serum C4 levels as biomarkers for SLE remains controversial, these markers are widely used in clinical practice (8–17). The recognition that complement and SLE are intimately associated, together with the questionable value of using serum C3 and serum C4 levels as biomarkers of lupus disease activity (8–17), led us to consider alternative measures of complement activation for monitoring patients with SLE (18–20). Proteolytic fragments of complement component C4, particularly C4d, are present on the surface of normal erythrocytes (21,22). Our group previously demonstrated that patients with SLE had significantly higher levels of erythrocyte-bound C4d (E-C4d) and lower levels of erythrocyte-expressing complement receptor 1 than did patients with other diseases and healthy control subjects (19). In addition, we observed that lupus disease activity correlated with reticulocyte C4d in a cross-sectional analysis and correlated serial measurements of E-C4d and reticulocyte C4d with disease activity in individual patients with SLE (20). In this longitudinal study, we assessed the utility of assays with E-C3d and E-C4d, as compared with the serum C3 and C4 assays in routine clinical use, as measures of lupus disease activity.