A positive correlation between obesity and the risk of acquiring asthma has been suggested by epidemiologic studies, but the mechanism underlying this relationship has not been established. The levels of leptin, a proinflammatory, satiety-controlling cytokine, are increased in the serum of obese individuals; therefore, we hypothesized that obesity promotes the development of asthma through leptin-induced augmentation of airway inflammation. The purpose of this study was to test this hypothesis by experimentally manipulating endogenous serum leptin levels and assessing their effects on markers of ozone-induced airway inflammation. Serum leptin was increased by feeding weanling C57BL/6J mice chow consisting of either 10 kilocalories or 45 kilocalories percentage fat for 20 weeks and was decreased by fasting mice for 18 h. Mice were subsequently exposed to 2 ppm ozone or filtered air for 3 h. Four hours later, blood was collected for assay of serum leptin and BAL was performed. Serum leptin increased from 6.7 ± 2.3 ng/mL in chow-fed mice to 12.5 ± 2.9 ng/mL and 22.9 ± 3.7 ng/mL (p < 0.005) in mice fed diets of 10% fat and 45% fat, respectively. Compared to air-exposed mice, ozone exposure caused an elevation in BAL protein, interleukin (IL)-6, and macrophage inflammatory protein (MIP)-2 in all three groups of mice. There was no significant effect of diet on BAL protein and IL-6, but MIP-2 levels were significantly higher in mice fed 10% fat (24.9 ± 3.9) or 45% fat (26.4 ± 3.2) than in chow-fed mice (7.5 ± 2.0 pg/mL) [p < 0.001]. Fasting decreased serum leptin from 14.4 ± 2.7 to 6.7 ± 2.2 ng/mL (p < 0.05). There was no significant effect of fasting on ozone-induced increases in BAL protein or IL-6, but fasting reduced BAL MIP-2 from 25.3 ± 8.3 to 6.7 ± 2.1 ng/mL (p < 0.05). The results of this study indicate that serum leptin modulates the levels of the chemokine MIP-2 following acute ozone exposure and suggest that the proinflammatory effects of leptin may contribute to the development of asthma in the obese.