To determine the role of interleukin (IL)-6 in the increased ozone (O₃)-induced inflammation and injury observed in obese versus lean mice, lean wildtype and leptin-deficient obese (ob/ob) mice were injected with anti-IL-6 antibody (Ab) or an isotype control Ab 24 hours before exposure to either O₃ (2 ppm for 3 h) or room air. Four or 24 hours after O₃ exposure, bronchoalveolar lavage (BAL) was performed and the lungs were harvested for Western blotting. Anti-IL-6 Ab caused substantial reductions in O₃-induced increases in BAL IL-6 in mice of both genotypes. Four hours following O₃, ob/ob mice had increased BAL neutrophils compared to controls and anti-IL-6-Ab virtually abolished this difference. At 24 hours, O₃-induced increases in BAL protein and BAL serum albumin were augmented in ob/ob versus wildtype mice and anti-IL-6-Ab ablated these obesity-related differences in epithelial barrier injury. O₃ increased tyrosine phosphorylation of STAT-3 and STAT-1. There was no effect of obesity on STAT-3 phosphorylation, whereas obesity decreased STAT-1 expression, resulting in reduced STAT-1 phosphorylation. IL-6 neutralization did not alter STAT-3 or STAT-1 phosphorylation in ob/ob or wildtype mice. O₃ increased BAL leukemia inhibitory factor (LIF) to a greater extent in obese than lean mice and LIF may account for effects on STAT phosphorylation. Our results suggest that IL-6 plays a complex role in pulmonary responses to O₃, a role that differs between wildtype and ob/ob mice. Moreover, obesity-related differences in activation of STAT proteins may contribute to some of the differences in the response of obese versus lean mice.