The serum antibody response and four different cellular immune responses (cytotoxic T cells, delayed-type hypersensitivity T cells, natural killer cells, and cytotoxic macrophage levels) induced in CBA/H mice were measured at different times after intranasal inoculation of a cold-adapted (ca) variant of influenza A virus, influenza virus A/Ann Arbor/6/60-ca, or the parental virus, influenza virus A/Ann Arbor/6/60. At the highest dose of virus inoculated (5 log10 50% tissue culture infective doses), all four cellular responses reached high levels in the lungs of both groups of mice, and serum antibody titers were detected on day 20 after inoculation of either virus. However, whereas extensive replication of the parental virus occurred in the mouse lungs, very limited replication of the ca variant was observed. Macroscopically, infection with the parental virus caused gross lung damage, whereas such damage was almost absent in mice inoculated with the ca variant. Inoculation of 2 to 5 log10 50% tissue culture infective doses of the parental virus induced high cytotoxic T-cell responses, whereas only the highest dose of the ca variant caused a clearly significant cytotoxic T-cell response. As an inoculum of 5 log10 50% tissue culture infective doses of the ca variant caused a substantial primary immune response without appreciable lung damage, the avirulence of the ca variant may be primarily related to its limited ability to replicate productively in mouse lungs.