MRL/Mp-lpr/lpr (MRL/lpr) mice develop anti-Sm Abs that bind the B and D proteins of the U1 and other U small nuclear ribonucleoproteins (snRNPs). Humans with SLE also develop anti-Sm, but in contrast to MRL/lpr mice, anti-Sm Abs in humans are virtually always accompanied by anti-snRNP Abs that bind the A and 70 kDa proteins of the U1 snRNP. In this study, we identified anti-U1 snRNP Abs in 60% of MRL/lpr mice (40 of 66 animals), with the earliest and most frequent response directed against the A protein. This response was either accompanied or closely followed by Abs to other snRNP proteins, including the 70-kDa protein of the U1 particle and the B and D proteins that represent the anti-Sm response. Other U snRNPs were rarely bound by these sera, analogous to previous observations in human SLE. Using in vitro translated 5' and 3' deletion mutants, we found that these early Abs principally bound an epitope on the COOH-terminal of the murine A protein. As shown previously, human sera with anti-U1 snRNP reactivity bind a similar epitope. In summary, we have shown that anti-snRNP Abs in MRL/lpr mice are composed of a linked group of specificities against proteins of the U1 snRNP particle, similar to human SLE. These observations, in conjunction with our previous findings that intact snRNPs are necessary for diversification of Abs in normal mice immunized with snRNPs, strongly suggests that intact U1 particles may be targets of the immune response in this disease.