Thermal injury induces immune dysfunction and alters numerous physiological parameters. Studies have proposed that genetics influence the outcome after traumatic injury and/or sepsis, however, the contribution of genetics to the immune-inflammatory response postburn has not been investigated. In this study, mice of three distinct genetic backgrounds (C57BL/6NCrlBR, BALB/cAnNCrlBR, and 129S6/SvEvTac) were subjected to thermal injury or a sham procedure, and 3 days later, blood and splenic immune cells (splenocytes and macrophages) were isolated for analysis. Splenocytes from the C57BL/6NCrlBR strain displayed suppressed splenic T cell proliferation postinjury, whereas the other strains were unaffected. Burn injury also induced a shift toward a Th2-type T-cell response (suppressed IFN-γ production) in the C57BL/6NCrlBR strain, but not in the other strains. Macrophages from C57BL/6NCrlBR and 129S6/SvEvTac mice were highly proinflammatory with elevated productive capacity for TNF-α and nitric oxide, whereas no such changes were observed in macrophages for BALB/cNCrlBR mice. C57BL/6NCRLBR macrophages produced increased IL-10 levels postburn, and BALB/cNCrlBR macrophages had suppressed IL-10 production postinjury. No differences in fasting blood glucose and insulin were observed after thermal injury. However, significant postburn weight loss was observed in the BALB/cNCrlBR and 12986/SvEvTac strains, but not in the C57BL/6NCrlBR strain. In summary, these findings support the concept that the immune-inflammatory response postburn is influenced by genetic make-up. Further elucidation of the influence of genetics under such conditions is likely to contribute to the improvement in existing, and development of new, therapeutic regimes for burn patients.