Adiponectin is an adipose-derived hormone with anti-inflammatory activity. Following subacute ozone exposure (0.3 ppm for 24-72 h), neutrophilic inflammation and IL-6 are augmented in adiponectin deficient (Adipo^-/-) mice. The IL-17/G-CSF axis is required for this increased neutrophilia. We hypothesized that elevated IL-6 in Adipo^-/- mice contributes to their augmented responses to ozone via effects on IL-17A expression. Therefore, we generated mice deficient in both adiponectin and IL-6 (Adipo^-/-IL-6^-/-) and exposed them to ozone or air. In ozone exposed mice, BAL neutrophils, IL-6, and G-CSF, and pulmonary Il17α mRNA expression were greater in Adipo^-/- versus wildtype mice, but reduced in Adipo^-/-IL-6^-/- versus Adipo^-/- mice. IL-17A+ F4/80+ cells and IL-17A⁺ T-cells were also reduced in Adipo^-/-IL-6^-/- versus Adipo^-/- mice exposed to ozone. Only BAL neutrophils were reduced in IL-6^-/- versus WT mice. In wildtype mice, IL-6 was expressed in Gr-1⁺F4/80^-CD11c^- cells, whereas in Adipo-/- mice, F4/80⁺CD11c⁺ cells also expressed IL-6, suggesting that IL-6 is regulated by adiponectin in these alveolar macrophages. Transcriptomic analysis identified serum amyloid A3 (Saa3), which promotes IL-17A expression, as the gene most differentially augmented by ozone in Adipo^-/- versus wildtype mice. After ozone, Saa3 mRNA expression was markedly greater in Adipo^-/- versus wildtype mice, but reduced in Adipo^-/-/IL-6^-/- versus Adipo^-/- mice. In conclusion, our data support a pivotal role of IL-6 in the hyperinflammatory condition observed in Adipo^-/- mice after ozone exposure, and suggest that this role of IL-6 involves its ability to induce Saa3, IL-17A and G-CSF.