Pregnancy is a delicate yet complex physiological process that requires fine-tuning of many factors (hormones, growth factors, cytokines, and receptors) between the mother and the conceptus to ensure the survival of the conceptus(es) to term. Any disturbance in the maternal-conceptus dialog can have detrimental effects on the affected conceptus or even the outcome of pregnancy as a whole. Being a litter-bearing species, such disruptions can lead to a loss of up to 45% of the totally healthy offspring during early (periattachment) and midgestation to late gestation in pigs. Although the exact mechanism is not entirely understood, several factors have been associated with the fetal loss including but not limited to uterine capacity, placental efficiency, genetics, nutrition, and deficits in vascularization at the maternal-fetal interface. Over the years, we investigated how immune cells are recruited to the porcine maternal-fetal interface and whether they contribute to vascularization. We also delineated how cytokines, chemokines, and cytokine destabilizing factors fine-tune inflammation and whether the cytokine shift from early to midpregnancy exists at the porcine maternal-fetal interface. Finally, we evaluated the role of microRNAs in regulating immune cell recruitment and their angiogenic functions during pregnancy. Collectively our research points out that the immune-angiogenesis axis at the porcine maternal interface is significantly involved in promoting new blood vessel development, regulating inflammatory responses and ultimately contributing to pregnancy success. In this review, we summarized current knowledge on spontaneous fetal loss in swine, with special attention to the mechanisms in immune reactivity and interplay at the maternal-fetal interface.