The hY RNAs form a macromolecular complex with the 60-kDa Ro protein and may in addition be bound by the La protein. In this study, we examine the autoantibody responses to the intact protein-RNA complexes in 18 subacute cutaneous lupus (SCLE), 10 discoid lupus (DLE), and 18 neonatal lupus erythematosus (NLE) sera. All SCLE and NLE serum samples precipitated all four of the Ro hY RNAs, whereas none of the DLE serum samples precipitated the hY RNAs. Among the SCLE and NLE sera, there was a significant association between the amount of Ro hY RNAs precipitated and the concurrent presence of anti-La antibodies in the sera (p = 0.008), consistent with the hypothesis that both the 60-kDa Ro and the La proteins can bind the Ro hY RNAs. There was no correlation between the amount of hY RNAs precipitated and the titer of antibodies to the 60-kDa Ro protein in enzyme-linked immunosorbent assay (ELISA). This may be due to a difference in the epitopes formed by the antigen in the respective assays. The autoantibody response to Ro in SCLE and NLE, which is generally detectable by both immunodiffusion and ELISA, is directed to all the subsets of the Ro protein-hY RNA complexes. The autoantibody response in DLE, though frequently detectable by ELISA, is not of sufficient concentration or affinity to precipitate the Ro protein-RNA complexes. The autoantibody response to Ro in SCLE and NLE may include antibodies to epitopes created by the complexing of the 60-kDa Ro protein with hY RNA.