Objective To investigate the prevalence and features of active human cytomegalovirus (HCMV) infection in children with systemic lupus erythematosus (SLE) and evaluate the diagnostic value of the HCMV using antigenemia assay, serum polymerase chain reaction (PCR) and serology test. Methods Twenty-one SLE children undergoing immunosuppressive therapy were enrolled in this study. Immunofluorescence assay, PCR and serology tests were used to determine HCMV pp65 and p72 antigens in leukocytes, HCMV DNA in sera, and HCMV specific IgM and IgG antibodies, respectively. As a control group, twenty-one immunocompetent children with skeletal malformation were involved in this study. Statistical analysis was performed using Chi-square test or Fisher's exact test (Systat, USA), P values less than 0.05 were considered significant.Results Active HCMV infection was diagnosed in 28.6% (6/21) of SLE patients, with none in the control group; the difference between the two groups was significant (P=0.027). Two out of 6 SLE patients developed active HCMV infection before immunosuppressive therapy and the remaining 4 patients developed SLE after immunosuppressive therapy. Among the 21 SLE children, HCMV pp65 antigenemia was detected in 5 patients, p72 antigenemia in 3 patients, serum HCMV DNA in 9 patients, serum HCMV-specific IgM in 2 patients, and IgG in 19 patients. The sensitivity and specificity for diagnosis of active HCMV infection were 83.3% and 100%, respectively for pp65 antigenemia; 50% and 100% for p72 antigenemia; 100% and 80% for serum PCR; 33.3% and 100% for HCMV IgM serology; 50% and 100% for HCMV IgG serology. Conclusions Compared with the control group, active HCMV infection is much more frequent in SLE children, and can occur before treatment with immunosuppressive agents, but most often occur after immunosuppressive therapy. In comparison with the other techniques used in this study, the pp65 antigenemia assay seems to be a better method for the early diagnosis and monitoring of active HCMV infection in children with SLE.