In the airways, inhibitory M2 muscarinic receptors (M2Rs) on parasympathetic nerves limit acetylcholine release. Viral infection causes M2R dysfunction, which increases acetylcholine release and leads to airway hyperreactivity. In these studies we tested the role of CD8+ T cells in parainfluenza virus-induced hyperreactivity and M2R dysfunction in normal guinea pigs and in guinea pigs previously sensitized to ovalbumin. Depleting CD8+ T cells prevented virus-induced M2R dysfunction and hyperreactivity in sensitized animals, but not in nonsensitized animals. Sensitization increased the number of eosinophils in close relation to the airway nerves where, when activated, they release major basic protein, which binds to and blocks the M2Rs. Regardless of sensitization, viral infection decreased the number of visible tissue eosinophils, likely reflecting eosinophil degranulation via cytolysis. Depleting CD8+ T cells prevented this virus-induced eosinophil degranulation. In addition, an antiviral effect of sensitization, which we previously showed to be eosinophil mediated, was again seen. This was prevented by depletion of CD8+ Tcells. Thus, CD8+ T cells play a role in airway hyperreactivity and M2R dysfunction of sensitized virus-infected guinea pigs by mediating eosinophil degranulation near airway nerves. In contrast, CD8+ T cells are not necessary for virus-induced hyperreactivity and M2R dysfunction in nonsensitized guinea pigs.