Interleukin-6(-)(1)(7)(4) (IL-6(-)(1)(7)(4)) and tumor necrosis factor alpha(-)(3)(0)(8) (TNFalpha(-)(3)(0)(8)) are high-cytokine-producing genotypes that are known to increase the susceptibility to infectious diseases, but their influence on cytokine production induced by respiratory viruses is unknown. We exposed human monocyte-derived macrophages from IL-6(-)(1)(7)(4), TNFalpha(-)(3)(0)(8), and normal genotype donors to different respiratory viruses. Respiratory syncytial virus (RSV) stimulation was associated with higher IL-6 concentrations in IL-6(-)(1)(7)(4) donors than in normal donors (P = 0.015); 2 of 7 (29%) polymorphic donors were poor responders compared with 6 of 7 (86%) normal donors (P = 0.002). Adenovirus, influenza virus, and RSV stimulations were associated with higher TNFalpha concentrations in TNFalpha(-)(3)(0)(8) donors than in normal donors (P = 0.03, <0.01, <0.01). A similar trend was seen with rhinovirus stimulation, but this was not significant. These results show that IL-6(-)(1)(7)(4) and TNFalpha(-)(3)(0)(8) gene polymorphisms lead to enhanced production of the respective cytokines when exposed to specific respiratory viruses. This, in turn, may influence the susceptibility to, severity of, and recovery from respiratory virus infections, or influence the immune response to and reactogenicity of viral vaccines.