Systemic Lupus Erythematosus (SLE) is a complex autoimmune disease. HTLV-1 Related Endogenous Sequence (HRES-1), a human endogenous retrovirus, produces 2 retroviral-like Gag capsid proteins (p8 and p15) that share significant sequence homology to the U1-subunit of the small ribonucleoprotein complex (U1sn-RNP), an autoantigen of lupus. The central hypothesis is that molecular mimicry between HRES-1 and U1sn-RNP serves as a priming event in SLE via the production of cross-reactive autoantibodies. Anti-HRES-1/U1sn-RNP serological responses in subjects with SLE and comparison populations were characterized. An overlapping peptide set mapping the HRES-1 p8 and p15 proteins was used. SLE subjects produce IgG to several regions of HRES-1. Healthy subjects or those with RA, HIV-1 infection, or HTLV-1-infection produced no significant anti-HRES-1 IgG. Anti-HRES-1 antibodies deposited in the kidneys of patients with SLE glomerulonephritis were identified. Our data suggests that HRES-1 plays a role in SLE by means of a molecular mimicry mechanism with U1sn-RNP.