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Summary: We previously reported that infection of different mouse strains with a recombinant HSV-1 expressing IL-2 (HSV-IL-2) caused CNS demyelination. Histologic examination of infected IL-2rα−/−, IL-2rβ−/−, and IL-2rγ−/− mice showed demyelination in the CNS of IL-2rα−/− and IL-2rβ−/− mice but not in the CNS of IL-2rγ−/−-infected mice. No demyelination was detected in mice infected with control virus. IL-2rγ−/− mice that lack type 2 innate lymphoid cells (ILC2s) and ILCs, play important roles in host defense and inflammation. We next infected ILC1−/−, ILC2−/−, and ILC3−/− mice with HSV-IL-2 or wild-type (WT) HSV-1. In contrast to ILC1−/− and ILC3−/− mice, no demyelination was detected in the CNS of ILC2−/−-sinfected mice. However, transfer of ILC2s from WT mice to ILC2−/− mice restored demyelination in infected recipient mice. CNS demyelination correlated with downregulation of CCL5 and CXCL10. This study demonstrates that ILC2s contribute to HSV-IL-2-induced CNS demyelination in a mouse model of multiple sclerosis.