Summary cDNA encoding a 70 kd protein (70K) associated with Ul small nuclear ribonucleoprotein(snRNP) was cloned from a human brain-stem library using autoantibodies from patients with connective tissue disease. The cDNA-derived amino acid sequence contains 23 residues homologous to a region of murine leukemia virus group-specific antigen p3Osas. The homology resides in an antigenic portion of the 70K protein and is defined by a core consensus sequence, ETPEEREERRR, that occurs as a tandem repeat in p30gag of most mammalian type C retroviruses. Anti-p3Wag antibodies recognized a recombinant ‘IOK-LacZ fusion protein as well as Ui snRNPs. Using synthetic peptides as competitors, we demonstrated that the region of homology encompasses the site of immunological cross-reactivity. Thus autoantibodies against Ul snRNPs were elicited by immunization with p30gag. On the basis of these findings, we suggest a role for retroviruses in the initiation of autoimmunity.