The Ro/SS-A (Ro) autoantigens consist of at least four immunologically distinct proteins which are recognized by autoantibodies typically found in sera from patients with primary Sjogren's syndrome and in subsets of patients with lupus erythematosus. We recently isolated a 1.9-kb human cDNA clone which encodes one of these Ro autoantigens. Synthetic oligonucleotides corresponding to the human Ro sequence were used to amplify the homologous gene from a murine B cell cDNA library using the polymerase chain reaction. The mouse cDNA-encoded amino acid sequence was found to be 94% homologous to the human Ro sequence and is 100% homologous to murine calreticulin, a high affinity calcium-binding protein which resides in the endoplasmic and sarcoplasmic reticulum. The amino acid sequence of rabbit calreticulin is 92% homologous to both murine calreticulin and human Ro. Onchocerca volvulus and Drosophila melanogaster also have molecules that are highly homologous to human Ro. In addition, human Ro has a molecular mass, isoelectric point, and significant amino acid sequence similar to the Aplysia californica snail neuronal protein 407. These homologies suggest that this Ro protein has a very basic cellular function(s) which may in part involve calcium binding.