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Stereotactic body radiation therapy (SBRT) can positively influence an antitumor immune response by inducing necrotic cell death. SBRT also been shown to eliminate tumors outside the radiation therapy field through an immune-mediated process known as the abscopal effect. Recent advances in immunotherapy may provide new therapeutic approaches for patients with liver cancer. Therefore, understanding the immune status of patients with cancer will likely guide how immunotherapy might be used in combination with SBRT. We hypothesized that we would observe changes in circulating blood immune cell populations of patients who received SBRT for liver tumors. Therefore, we assessed 110 immunophenotypes in the peripheral blood of 10 patients with liver cancer or metastases to the liver pretreatment and 2 posttreatment time points. Patients with liver cancer and metastatic patients both exhibited several immunophenotypic abnormalities at baseline compared with a group of healthy volunteer controls. In longitudinal studies, SBRT caused a specific reduction in CD3 + T cell counts and immature CD56 br CD16 - NK cell counts. The immune profiling and potential identification of circulating biomarkers shown here could lead to the design of combinatorial approaches with SBRT and immunotherapy to optimize the timing of treatment and direct the most effective immunotherapy with SBRT.