Purpose Chronic radiation exposure poses threats to cellular damage and carcinogenesis to military members working in multiple environments such as high altitude high-latitude air travel, nuclear submarine duty, or land environments with depleted uranium or dirty bomb detonations. Efforts to develop effective countermeasures have been hampered by the absence of working animal models demonstrating pathology from chronic radiation exposure. The purpose of this pilot study is to investigate large animal pathology after exposure to a fractionated series of x-rays delivered over a course of eight weeks. Methods Six swine underwent different doses of an 8-week fractionated x-ray series gradient frontally directed to have maximal exposure at the head and complete sparing of the erythropoietic hind limbs totaling 0.9-3.4 Gray exposure at the heart and 0.1 Gray at the liver. Two control swine underwent no radiation exposure but otherwise identical test conditions. Blood draws were performed each week immediately prior to radiation exposure, to measure complete blood counts and plasma biomarkers. At week 12, necropsy and organ harvest was performed to analyze gross and microscopic histopathology. Results There were no differences in baseline hematocrit. All doses resulted in rapid and persistent reduction in lymphocytes, although platelet and white blood cell counts exhibited varying responses relative to controls. Lymphocyte depletion was observed in a dose-dependent manner, starting at week 1 and remaining low during the 8 weeks of radiation and did not improve during the 4 weeks post radiation. All doses resulted in transient inflammation of the liver with normalization of alanine transaminase enzymes four weeks after cessation of irradiation. Non-irradiated control swine did not show signs of liver inflammation. Liver tissue from irradiated swine showed evidence of inflammation and fibrosis. Conclusion In this pilot study, chronic exposure to low dose x-ray ionizing radiation resulted in porcine pathology capable of allowing future radiation exposure countermeasures studies. The eight-week exposure resulted in acute and persistent decrease in lymphocytes in a dose-dependent manner as well as an elevation of alanine transaminase (ALT) without elevations in aspartate amino-transferase (AST) or alkaline phosphatase (AP), which is consistent with nonalcoholic fatty liver disease. Swine metabolism differs from humans in a way that prevents fat accumulation in the liver. Noting fatty liver disease in healthy young adult swine during radiation exposure highlights the potential risk to active-duty members operating in such environments. More investigation with a longer monitoring period will be needed to fully characterize the impact of chronic exposure to low dose ionizing radiation on lymphocytes. Fractionated, frontally-directed x-ray gradients provide a viable large animal model to test and develop countermeasures to chronic radiation exposure. Disclaimer The views expressed in this material are those of the author(s) and do not necessarily reflect the official policy or position of the Department of the Air Force, the Department of Defense, or the U.S. government. The animals involved in this study were procured, maintained, and used in accordance with the Laboratory Animal Welfare Act of 1966, as amended, and the Guide for the Care and Use of Laboratory Animals, National Research Council. The work reported herein was performed under United States Air Force Surgeon General-approved Research Protocol Number FDG20230029A.