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M ucoid, mucA mutant Pseudomonas aeruginosa cause chronic lung infections in cystic fibrosis (CF) patients and are refractory to phagocytosis and antibiotics. Here we show that mucoid bacteria perish during anaerobic exposure to 15 mM nitrite (NO₂^–) at pH 6.5, which mimics CF airway mucus. Killing required a pH lower than 7, implicating formation of nitrous acid (HNO₂) and NO, that adds NO equivalents to cellular molecules. Eighty-seven percent of CF isolates possessed mucA mutations and were killed by HNO₂ (3-log reduction in 4 days). Furthermore, antibiotic-resistant strains determined were also equally sensitive to HNO₂. More importantly, HNO₂ killed mucoid bacteria (a) in anaerobic biofilms; (b) in vitro in ultrasupernatants of airway secretions derived from explanted CF patient lungs; and (c) in mouse lungs in vivo in a pH-dependent fashion, with no organisms remaining after daily exposure to HNO₂ for 16 days. HNO₂ at these levels of acidity and NO₂^– also had no adverse effects on cultured human airway epithelia in vitro. In summary, selective killing by HNO₂ may provide novel insights into the important clinical goal of eradicating mucoid P. aeruginosa from the CF airways.