The immunoregulatory functions of IL-4 and IL-5 have identified these cytokines as primary targets for the resolution of airways inflammation and bronchial hyperreactivity in asthma. However, the individual contribution of each of these cytokines and of IL-5-regulated eosinophilia to the induction of airways hyperreactivity in mouse models of asthma remains highly controversial. In this investigation, we have used IL-4-and IL-5-deficient mice of the same genetic background in combination with inhibitory mAbs to these cytokines to identify unequivocally the contribution of these factors to the induction of airways hyperreactivity. Sensitization and aeroallergen challenge of wild-type mice with OVA induced pathological changes to the respiratory epithelium, airways eosinophilia, and hyperreactivity to β-methacholine. Inhibition of the actions of IL-4 and/or IL-5 did not abolish airways hyperreactivity, and in the case of IL-4-deficient mice pretreated with anti-IL-5 mAb, airways hyperreactivity persisted in the absence of pronounced airways inflammation. Airways hyperreactivity was abolished only by anti-CD4+ mAb treatment. However, aeroallergen challenge of IL-5−/− mice showed that morphologic changes to the airways were critically linked to IL-5 and eosinophilia. This investigation demonstrates the existence in BALB/c mice of a novel CD4+ T cell pathway for modulating airways hyperreactivity. These findings may provide an explanation for the dissociation of airways eosinophilia from the development of airways hyperreactivity observed in some cases of asthma and in animal models of this disease.