Members of the IL-1 family play protective and regulatory roles in immune defense against the opportunistic mold Aspergillus fumigatus. In this study, we investigated the IL-1 family member IL-33 in lung defense against A. fumigatus. IL-33 was detected in the naive lung, which further increased after exposure to A. fumigatus in a dectin-1–independent manner. Mice deficient in the receptor for IL-33 (Il1rl1−/−) unexpectedly demonstrated enhanced lung clearance of A. fumigatus. IL-33 functioned as a negative regulator of multiple inflammatory cytokines, as IL-1α, IL-1β, IL-6, IL-17A, and IL-22 were significantly elevated in fungal-exposed Il1rl1−/− mice. Subsequently, IL-33 administration to normal mice attenuated fungal-induced IL-17A and IL-22, but not IL-1α, IL-1β, or IL-6, production. IL-33–mediated regulation of IL-17A and IL-22 did not involve the modulation of IL-23 but rather PGE 2; PGE 2 was significantly increased in fungal-exposed Il1rl1−/− mice, and normal mice produced less PGE 2 after fungal exposure when administered IL-33, suggesting that IL-33–mediated regulation of IL-17A and IL-22 occurred at the level of PGE 2. This was confirmed by in vivo cyclooxygenase 2 inhibition, which attenuated fungal-induced IL-17A and IL-22, as well as IL-1α, IL-1β, and IL-6, production in Il1rl1−/− mice, resulting in impaired fungal clearance. We also show that a PGE 2 receptor agonist increased, whereas a PGE 2 synthase inhibitor decreased, the levels of IL-17A and IL-22 but not IL-1α, IL-1β, or IL-6. This study establishes novel mechanisms of innate IL-17A/IL-22 production via PGE 2 and regulation of the PGE 2/IL-17A/IL-22 axis via IL-33 signaling during lung fungal exposure.