Due to growing antibiotic resistance, pneumonia caused by Pseudomonas aeruginosa is a major threat to human health and is driving the development of novel anti-infectious agents. Preventively or curatively administered pathogen-specific therapeutic antibodies (Abs) have several advantages, including a low level of toxicity and a unique pharmacological profile. At present, most Abs against respiratory infections are administered parenterally; this may not be optimal for therapeutics that have to reach the lungs to be effective. Although the airways constitute a logical delivery route for biologics designed to treat respiratory diseases, there are few scientific data on the advantages or disadvantages of this route in the context of pneumonia treatment. The objective of the present study was to evaluate the efficacy and fate of an anti-P. aeruginosa Ab targeting pcrV (mAb166) as a function of the administration route during pneumonia. The airway-administered mAb166 displayed a favorable pharmacokinetic profile during the acute phase of the infection, and was associated with greater protection (relative to other delivery routes) of infected animals. Airway administration was associated with lower levels of lung inflammation, greater bacterial clearance, and recruitment of neutrophils in the airways. In conclusion, the present study is the first to have compared the pharmacokinetics and efficacy of an anti-infectious Ab administered by different routes in an animal model of pneumonia. Our findings suggest that local delivery to the airways is associated with a more potent anti-bacterial response (relative to parenteral administration), and thus open up new perspectives for the prevention and treatment of pneumonia with Abs.