During early pregnancy in ruminants, a Type I IFN (IFN-) signals from the conceptus to the mother to ensure the functional survival of the corpus luteum. IFN- operates through binding to the Type I IFN receptor. Here we have explored the possibility that IFNAR2, one of the two subunits of the receptor, might interact with hitherto unknown signal transduction factors in the uterus which link IFN action to pathways other than the well-established Jak-STAT pathways. A yeast two-hybrid screen of an ovine endometrial cDNA library with the carboxyl terminal 185 amino acids of ovIFNAR2 as bait identified stress-activated protein kinase (SAPK) interacting protein 1 (ovSin1) as a protein that bound constitutively through its own carboxyl terminus to the receptor. OvSin1 is a little studied 522 amino acid long polypeptide (Mr 59,200), which is highly conserved across vertebrates, but which has identifiable orthologs in Drosophila and yeast. It appears to be expressed ubiquitously in mammals, although at low abundance, in a wide range of mammalian tissues in addition to endometrium. Sin1 mRNA occurs in at least two alternatively spliced forms, the smaller of which lacks a 108 bp internal exon. OvSin1, although not exhibiting features of a membrane-spanning protein, like IFNAR2, is concentrated predominantly in luminal and glandular epithelial cells of the uterine endometrium. When ovSin1 and ovIFNAR2 are co-expressed, the two proteins can be co-immunoprecipitated and co-localize to the plasma membrane and to perinuclear structures. Sin1 provides a possible link between Type I IFN action, stress-activated signaling pathways, and control of prostaglandin production.