To determine whether rhinovirus infection induced a systemic cellular immune response in humans, specific antigen-stimulated blastogenesis, natural killer cell activity, and mitogen-stimulated production of interleukin-2 and interferon-gamma by peripheral blood mononuclear cells (PBMC) were quantified during experimental rhinovirus infection of normal volunteers. Phytohemagglutinin-stimulated interleukin-2 production by PBMC collected on day 5 after rhinovirus inoculation was increased fourfold compared with production by PBMC collected before rhinovirus challenge (P less than .05); phytohemagglutinin-stimulated interferon-gamma production was doubled (P less than .05). An inverse relationship was observed between the increase in interleukin-2 production and both nasal mucus production (P less than .02) and the number of days virus was cultured from nasal washings (P less than .02). Natural killer cell-mediated cytotoxicity of PBMC collected on day 5 after rhinovirus challenge was also increased (P less than .01) compared with preinfection levels, as was specific antigen-stimulated blastogenesis on day 21 (P less than .05). The extent of blastogenic response correlated directly with both mucus production (P less than .05) and the number of days virus was cultured from nasal washings (P less than .05). These observations are consistent with the hypothesis that rhinovirus infection results in activation of a systemic cellular immune response.