Elimination of CD4+helper T cells by treatment with monoclonal antibodies (mcAb) in vivo has been used as a new mode of immunosuppression in organ transplantation and autoimmune diseases. To explore the potential risks of this therapeutic approach we have studied antiviral responses in mice depleted of CD4+T cells.Depletion of CD4+T cells in vivo completely suppressed the generation of a primary virus-specific cytotoxic response. Injection of high doses of recombinant interleukin-2 (rIL-2) given after virus immunization restored the responsiveness of helper cell—depleted mice to virus-expressing target cells, suggesting a crucial role of IL-2 in antiviral defense mechanisms. In contrast to primary responses, memory cytolytic responses to viral antigens persisted despite depletion of >90% of CD4+helper T cells. The generation of such memory cytotoxic responses was dependent upon help provided by CD4+lymphocytes surviving the antibody therapy. After antibody treatment, frequencies of virus-specific helper cells were minimal in primed mice, excluding insufficient helper cell elimination as the reason for the persistence of memory responses. Data presented here suggest that there exist distinct helper pathways in primary and secondary cytolytic antiviral responses that might represent several subsets of helper T cells as well as differences in helper signals required by distinct effector cells.