In pregnant mares, the complex relationship between the immune and hormonal systems is crucial for maintaining pregnancy and ensuring fetal health. In high-risk pregnancies, ascending placentitis is a leading cause of late-term pregnancy loss in mares. Additionally, neonatal foals are highly vulnerable to infections by opportunistic intracellular pathogens, making an effective cytotoxic immune response essential for protection. In my first study, I investigated the dynamics of hormone-immune and hormone-hormone associations throughout normal pregnancy in mares. Blood samples were longitudinally collected from pre-ovulation to late gestation. A gestational-age-specific modulation of immune cell distribution was observed, particularly a rise in CD4 T cells and a decline in B cells at 90 days of gestation, which correlated with levels of equine chorionic gonadotropin (eCG), progesterone (P4), 5α-dihydroprogesterone (DHP), and estrone-sulfate. Later in gestation (210 days), this pattern reversed, with peak B cell distribution and a concurrent decrease in CD4 T cells. This study revealed complex hormone-immune associations, especially during early and mid-pregnancy, suggesting that a tightly regulated hormonal environment may orchestrate immune modulation to support pregnancy. In my second study, I aimed to identify blood parameters associated with early events of naturally-occurring ascending placentitis. A cohort of 24 mares (12 mares with placentitis vs 12 control mares) was evaluated through reproductive ultrasonography and serial blood sampling. Early stages of ascending placentitis did not appear to induce obvious systemic immunological or inflammatory changes, with the exception of decreased albumin levels. Interestingly, the feto-placental unit appeared to be highly responsive, as evidenced by significant hormonal alterations. Mares with placentitis showed a markedly reduced DHP/20α-DHP ratio and lower estradiol-17β concentrations. These hormonal changes, particularly when combined with reduced albumin levels, demonstrated strong predictive value for diagnosing placentitis. A follow-up analysis stratified by placentitis severity revealed additional hormonal disruptions, further reinforcing the diagnostic value of hormonal parameters, even in the absence of overt systemic inflammation. In my third study, I addressed the immune cytotoxic response in foals by investigating potential age-dependent limitations of three key immune cell types: CD8 cytotoxic T cells, T regulatory cells (Tregs), and monocyte-derived macrophages (mMOs) in neonates (4 days old), foals (35 days old), and adult horses. Neonatal and foal CD8 T cells demonstrated adult-like proliferative capacity but produced significantly lower cytokine levels. IFN-γ production was notably enhanced upon IL-12 stimulation, indicating a capacity for functional augmentation. Circulating Treg frequencies were higher in neonates and foals than adults. Additionally, mMOs from neonates and foals mounted an adult-like IFN-γ response to CpG-ODN stimulation, while failing to respond to other stimuli, including inactivated Rhodococcus equi, rotavirus, and Escherichia coli. Collectively, these studies provide novel insights into the immune and hormonal adaptations that support equine pregnancy and the developmental trajectory of neonatal immunity.