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Natural killer (NK) cells are innate lymphoid cells that protect a host from viral infections and malignancies. MicroRNA‐146a (miR‐146a) is an important regulator of immune function that is highly expressed in NK cells and is further upregulated during murine cytomegalovirus (MCMV) infection. Here we utilized mice with a global targeted deletion of miR‐146a to understand its impact on the innate immune responses to MCMV infection. MiR‐146a−/− mice were protected from lethal MCMV infection, which was intrinsic to the hematopoietic compartment based on bone marrow chimera experiments. NK cell depletion abrogated this protection, implicating NK cells as critical for the miR‐146a−/− protection from MCMV. Surprisingly, NK cells from miR‐146a‐deficient mice were largely similar to control NK cells with respect to development, maturation, trafficking, and effector functions. However, miR‐146a−/− mice had increased NK cell numbers and frequency of the most mature Stage IV (CD27−CD11b+) NK cells in the liver at baseline, enhanced STAT1 phosphorylation, and increased selective expansion of Ly49H+ NK cells and T cells during MCMV infection. This study demonstrates a critical role for miR‐146a in the host response to MCMV, arising from mechanisms that include increased NK cell numbers and early T‐cell expansion. [ABSTRACT FROM AUTHOR]