Recent research has supported that a variety of cytokines play important roles during radiation-induced lung toxicity. The present study is designed to investigate the differences in early cytokine induction after radiation in sensitive (C57BL/6) and resistant mice (C3H). Twenty-two cytokines in the lung tissue homogenates, bronchial lavage (BAL) fluids, and serum from 3, 6, 12, 24 hrs to 1 week after 12 Gy whole lung irradiation were profiled using a microsphere-based multiplexed cytokine assay. The majority of cytokines had similar baseline levels in C57BL/6 and C3H mice, but differed significantly after radiation. Many, including granulocyte colony-stimulating factor (G-CSF), interleukin-6 (IL-6), and keratinocyte-derived chemokine (KC) were elevated significantly in specimens from both strains. They usually peaked at about 3-6 hrs in C57BL/6 and 6-12 hrs in C3H. At 6 hrs in lung tissue, G-CSF, IL-6, and KC increased 6, 8, and 11 fold in C57BL/6 mice, 4, 3, and 3 fold in the C3H mice, respectively. IL-6 was 10-fold higher at 6 hrs in the C57BL/6 BAL fluid than the C3H BAL fluid. MCP-1, IP-10, and IL-1alpha also showed some differences between strains in the lung tissue and/or serum. For the same cytokine and within the same strain of mice, there were significant linear correlations between lung tissue and BAL fluid levels (R2 ranged 0.46-0.99) and between serum and tissue (R2 ranged 0.56-0.98). Radiation induced earlier and greater temporal changes in multiple cytokines in the pulmonary fibrosis sensitive mice. Positive correlation between serum and tissue levels suggests that blood may be used as a surrogate marker for tissue.