The role of mononuclear phagocytes in various phases of the acute lymphocytic choriomeningitis virus (LCMV) infection was studied. The anti-macrophage agent carrageenan delayed virus clearance. Carrageenan was most effective when given before virus inoculation, suggesting that it interfered with early events in the host response to the virus. Correspondingly, carrageenan enhanced early virus multiplication. Pretreatment with carrageenan apparently did not inhibit induction of the T-cell response and had little or no direct effect on T-cell-dependent anti-viral activity. The LCMV-induced natural killer response was also unimpaired by this treatment. Taken together, these findings suggest that resident macrophages constitute a barrier to the initial multiplication of LCMV. A breakdown of this macrophage barrier results in a more disseminated infection, which the specific immune response has difficulty in eliminating. Adoptive transfer experiments with pre-irradiated recipients showed that T-cell-dependent virus clearance required interaction between donor-derived primary immune spleen cells and radiosensitive host cells. T cells did not seem to constitute the radiosensitive host component, since athymic (nude) mice functioned well as recipients. Together with previously published data, this finding strongly suggests that T-cell-dependent virus clearance involves cooperation between T cells and non-committed cells, probably monocytes.