Background: SmD1-amino-acid 83-119 peptide (SmD1(83-119)) is the major epitope of Smith (Sm) antigen, which is specific for adult systemic lupus erythematosus (SLE). The anti-SmD1(83-119) antibody has exhibited higher sensitivity and specificity than anti-Sm antibody in diagnosing adult SLE. However, the utility of anti-SmD1(83-119) antibodies remains unclear in children with SLE (cSLE). This study aimed to assess the characteristics of anti-SmD1(83-119) antibody in the diagnosis of cSLE. Methods: Samples from 242 children with different rheumatological and immunological disorders, including autoimmune diseases (SLE [n = 46] and ankylosing spondylitis [AS, n = 11]), nonautoimmune diseases (Henoch-Schonlein purpura [HSP, n = 60], idiopathic thrombocytopenia purpura [n = 27], hematuria [n = 59], and arthralgia [n = 39]) were collected from Shanghai Children's Medical Center from March 6, 2012 to February 27, 2014. Seventy age-and sex-matched patients were enrolled in this study as the negative controls. All the patients' sera were analyzed for the anti-SmD1(83-119), anti-Sm, anti-U1-nRNP, anti-double-stranded DNA (dsDNA), anti-nucleosome, anti-SSA/Ro60, anti-SSA/Ro52, anti-SSB, anti-Scl-70, and anti-histone antibodies using the immunoblotting assay. The differences in sensitivity and specificity between anti-SmD1(83-119) and anti-Sm antibodies were compared by Chi-square test. The correlations between anti-SmD1(83-119) and other auto-antibodies were analyzed using the Spearman's correlation analysis. A value of P < 0.05 was considered statistically significant. Results: Thirty-six out of 46 patients with cSLE were found to be positive for anti-SmD1(83-119), while 12 patients from the cSLE cohort were found to be positive for anti-Sm. Compared to cSLE, it has been shown that anti-SmD1(83-119) was only detected in 27.3% of patients with AS and 16.7% of patients with HSP. In comparison with anti-Sm, it has been demonstrated that anti-SmD1(83-119) had a higher sensitivity (78.3% vs. 26.1%, chi(2) = 25.1, P < 0.05) and a lower specificity (90.8% vs. 100%, chi(2) = 13.6, P < 0.05) in the diagnosis of cSLE. Further analysis revealed that anti-SmD1(83-119) antibodies were positively correlated with anti-dsDNA, anti-nucleosome, and anti-histone antibodies in cSLE. Moreover, it has been clearly shown that anti-SmD1(83-119) was more sensitive than anti-Sm in discriminating autoimmune diseases from nonautoimmune disorders in patients with arthralgia or hematuria. Conclusions: Measurement of anti-SmD1(83-119) in patients with cSLE has a higher sensitivity and a marginally lower specificity than anti-Sm. It has been suggested that inclusion of anti-SmD1(83-119) testing in the integrated laboratory diagnosis of cSLE may significantly improve the overall sensitivity in child populations.