Ubiquitin cross-reactive protein (UCRP) is a functional ubiquitin homolog synthesized by the ruminant endometrium in response to conceptus-derived interferon-tau (IFNτ). Progesterone is required for IFNτ to exert antiluteolytic actions on the endometrium. Therefore, this study was designed to determine whether progesterone is requisite for IFNτ induction of UCRP expression within the ovine uterus. Cyclic ewes were ovariectomized and fitted with intrauterine (i.u.) catheters on Day 5 and treated daily with steroids (i.m.) and protein (i.u.) as follows: 1) progesterone (P, Days 5–24) and control serum proteins (CX, Days 11–24); 2) P and ZK 137.316 (ZK; progesterone receptor antagonist, Days 11–24) and CX proteins; 3) P and recombinant ovine IFNτ (roIFNτ, Days 11–24); or 4) P and ZK and roIFNτ. All ewes were hysterectomized on Day 25. In P-treated ewes, roIFNτ increased endometrial UCRP mRNA and protein levels. However, administration of ZK to ewes ablated roIFNτ induction of UCRP. Recombinant ovine IFNτ induced expression of UCRP mRNA in progestinized endometrial luminal (LE) and glandular (GE) epithelium as well as in both stratum compactum and spongiosum layers of the stroma (ST). Progesterone receptor protein was located in endometrial ST, but not in LE and GE from these ewes. Results support the hypothesis that progesterone is required for IFNτ induction of type I IFN-responsive genes, such as UCRP, in the ruminant uterus.