Psychosocial factors moderate the expression of illness during upper respiratory virus infections but past attempts to define mediational pathways were not successful. Here, we used a model of experimental rhinovirus infection in humans to evaluate three proinflammatory cytokines for their potential role in mediating the previously documented association between positive emotional style and illness. After assessing emotional style in 327 healthy adults, each was exposed to one of two strains of rhinovirus and followed for 5 days in quarantine. Symptoms/signs, nasal lavage IL-1beta, IL-6, and IL-8 protein, and viral shedding were assessed at baseline and on each of the 5 days after exposure. Virus-specific antibody was assessed at baseline and 28 days after challenge. An analysis of the data for 234 subjects with documented infection showed that nasal IL-1beta, IL-6, and IL-8 protein levels were all associated with greater illness expression but IL-6 was by far the best predictor of nasal signs and symptoms. Lower positive emotional style was associated with greater objective and subjective markers of illness and these associations were decreased substantially by controlling for IL-6 but not for IL-1beta or IL-8. These results are consistent with the hypothesis that IL-6 acts as a biological mediator in linking positive emotional style to illness expression during rhinovirus infection.