Objective To investigate the presentationand significance of circulating autoantibodies to erythropoietin receptor (EPOR) in sera from patients with systemic lupus erythematosus (SLE). Methods One hundred and twenty-four consecutive patients with SLE, seven with autoimmune hemolytic anemia (AIHA), 19 patients with iron deficiency anemia (IDA) and 45 normal individuals were involved in this study. In all patients with SLE, the disease activity was evaluated using the European consensus Lupus Activity Measurement scale. Antibodies to EPOR were detected by enzyme-linked immunosorbent assay (ELISA). All data were tested with Chi-squared or Student's t tests by SPSS software. Results A higher frequency of antibodies to EPOR were detected in SLE patients than healthy controls (20.2% vs 2.2%, P=0.004), however, they could not be detected in AIHA and IDA patients. Moreover, anti-EPOR antibodies were detected in 17 (33.3%) of 51 SLE patients with anemia, compared with that in 8 (11.0%, P=0.002) of 73 patients without anemia. Furthermore, patients with antibodies to EPOR had more severe anemia and often presented as microcytic anemia (P =0.005) than those without anti-EPOR antibodies. Finally, anti-EPOR antibodies seemed to be more likely to occur in patients with skin rash (P=0.014), low levels of C3 component of complement (P=0.01), positive anti-dsDNA antibodies (P=0.000) and higher disease activity scores (P= 0.024). Conclusion The higher incidence of antibodies to EPOR in SLE patients with anemia suggest that anti-EPOR antibodies might play a vital role in the development of anemia in SLE patients. Thus, detecting anti-EPOR antibodies in SLE patients with anemia may be helpful.