The transcription of human endogenous retrovirus E (HERV-E) clone 4-1 was determined in peripheral blood mononuclear cells (PBMC) of patients with systemic lupus erythematosus (SLE). However, the contribution of HERV-E clone 4-1 expression in the development of SLE remains unclear. Blood plasma and PBMC from 55 patients with SLE and a control group of 35 healthy individuals were collected. Blood plasma concentration of five antinuclear antibodies including anti-U1 ribonucleoprotein (RNP), anti-Sm, anti-Scl-70, anti-single-stranded DNA (ssDNA), and anti-double-stranded DNA (dsDNA) was analyzed by enzyme-linked immunosorbent assay (ELISA). Total RNA was isolated from PBMC and reverse transcribed into cDNA. The number of copies of HERV-E clone 4-1 gag transcript in PBMC was determined by real-time quantitative polymerase chain reaction (RQ-PCR) analysis. Spearman statistical analysis indicated that blood plasma concentrations of anti-U1 RNP and anti-Sm antibodies may correlate with PBMC transcript levels of HERV-E clone 4-1 gag sequence (R = 0.775, p < 0.000001; R = 0.698, p < 0.000001, respectively). Our observations suggest that the expression of HERV-E clone 4-1 might be associated with production of anti-U1 RNP and anti-Sm antibodies in patients with SLE.