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Several immune cell populations participate in the development of radiation-induced cardiac fibrosis. However, the underlying mechanism remains to be elucidated. Male C57BL/6 mice (8–12 weeks old) were anesthetized and exposed to a single cardiac radiation dose of 20 Gy using the small-animal radiation research platform. We conducted echocardiography and histological analysis to identify cardiac fibrosis from a functional and pathological perspective. Time-of-flight mass cytometry (CyTOF) was used to describe the compositional changes of immune cells 1, 4, and 8 weeks after cardiac irradiation in mouse peripheral blood and cardiac tissue samples. Real-time quantitative polymerase chain reaction (RT-qPCR) was used to measure CD14 and CD105 mRNA levels from peripheral blood cells in eight patients who received thoracic radiotherapy 6 months ago. We observed reduced cardiac systolic function and increased collagen deposition in cardiac tissue after irradiation. Transforming growth factor-β, tumor necrosis factor-α, and interleukin-6 expression significantly elevated in the plasma. We identified a significant increase in CD45+immune cell levels four weeks after cardiac irradiation using CyTOF, and neutrophil, monocyte, and macrophage levels elevated in blood samples after cardiac irradiation (four weeks). In cardiac tissue samples, monocyte and macrophage levels increased after cardiac irradiation (four weeks) compared with control group. Macrophages and monocytes were further analyzed, and the proportion of Ly6ChiCD103+myeloid cells increased after cardiac irradiation in tissue samples (four weeks). RT-qPCR revealed that CD14 expression was higher in patients with cardiac injured group than in the control group (Previous studies reported that Ly6Chimonocytes in mice are similar to CD14 + CD16−monocytes in humans). We found that Ly6ChiCD103+myeloid cells are critical subsets in radiation-induced cardiac fibrosis and might play protective roles in the process. Ly6ChiCD103+myeloid cells may be considered an early biomarker for detecting radiation-induced cardiac fibrosis.