Recent studies have revealed that the human and non-rodent mammalian airway mucosa contains an oxidative host defense system. This three-component system consists of hydrogen peroxide (H2O2)-producing enzymes dual oxidase (Duox) 1 and 2, thiocyanate (SCN-), and secreted lactoperoxidase (LPO). The LPO-catalyzed reaction between H2O2 and SCN- yields the bactericidal hypothiocyanite (OSCN-) in airway surface liquid (ASL). Although SCN- is the physiological substrate of LPO, the Duox/LPO/halide system can also generate hypoiodous acid (HOI) when the iodide (I-) concentration is elevated in ASL. Since HOI, but not OSCN-, inactivates respiratory syncytial virus (RSV) in cell culture, we used a lamb model of RSV to test whether potassium iodide (KI) could enhance this system in vivo. Newborn lambs received KI by intragastric gavage or were left untreated prior to the intratracheal inoculation of RSV. The KI treatment led to a 10-fold increase in ASL I- concentration, and this I- concentration was ~30-fold higher than that measured in the serum. Also, expiratory effort, gross lung lesions, and pulmonary expression of an RSV antigen and interleukin-8 were reduced in the KI-treated lambs as compared to non-treated controls. Inhibition of LPO significantly increased lesions, and RSV mRNA and antigen. Similar experiments in 3-week-old lambs also demonstrated that KI administration was associated with reduced gross lesions, decreased RSV titers in bronchoalveolar lavage fluid, and reduced RSV antigen expression. Overall these data indicate that high-dose KI supplementation can be used in vivo to lessen the severity of RSV infections, potentially through the augmentation of mucosal oxidative defenses.