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T o investigate the function of prostaglandin H synthase-1 and synthase-2 (PGHS-1 and PGHS-2) in the normal lung and in allergic lung responses, we examined allergen-induced pulmonary inflammation and airway hyperresponsiveness in wild-type mice and in PGHS-1^–/– and PGHS-2^–/– mice. Among nonimmunized saline-exposed groups, we found no significant differences in lung function or histopathology, although PGE₂ was dramatically reduced in bronchoalveolar lavage (BAL) fluid from PGHS-1^–/– mice, relative to wild-type or PGHS-2^–/– mice. After ovalbumin sensitization and challenge, lung inflammatory indices (BAL cells, proteins, IgE, lung histopathology) were significantly greater in PGHS-1^–/– mice compared with PGHS-2^–/– mice, and both were far greater than in wild-type mice, as illustrated by the ratio of eosinophils in BAL fluid (8:5:1, respectively). Both allergic PGHS-1^–/– and PGHS-2^–/– mice exhibited decreased baseline respiratory system compliance, whereas only allergic PGHS-1^–/– mice showed increased baseline resistance and responsiveness to methacholine. Ovalbumin exposure caused a modest increase in lung PGHS-2 protein and a corresponding increase in BAL fluid PGE₂ in wild-type mice. We conclude that (a) PGHS-1 is the predominant enzyme that biosynthesizes PGE₂ in the normal mouse lung; (b) PGHS-1 and PGHS-2 products limit allergic lung inflammation and IgE secretion and promote normal lung function; and (c) airway inflammation can be dissociated from the development of airway hyperresponsiveness in PGHS-2^–/– mice.