SummaryPretreatment of mice with cyclophosphamide (CY) increases susceptibility of adult mice to herpes simplex type I (HSV‐I) infection. In searching for a CY sensitive mechanism, our attention has been focused on natural killer (NK) cells. Activity of these cells was increased in spleens of adult mice after inoculation with HSV‐I and depressed after CY administration. The timing of recovery of NK cell activity after the administration of CY, was consistent with a role for these cells in collaboration with immune T lymphocytes when transferred to pre‐treated, virus infected animals. It is postulated that sensitized T lymphocytes reacting with virus antigens release products that activate macrophages which in turn produce interferon. Interferon increases NK cell activity and NK cells inhibit viral replication. A correlation between resistance to HSV‐I infection and NK cell activity of CBA or C57BL/10 mice was found. It is suggested that NK cells play a role in defence, not only against tumour cells, but also against a wide range of infective