Rationale: Murine models demonstrate a synergistic production of reactive oxygen species upon co-exposure to diesel exhaust particles and endotoxin. Objectives: It was hypothesized that co-exposure to traffic-related particles and endotoxin would have an additive effect on persistent wheezing during early childhood. Methods: Persistent wheezing at age 36 months was assessed in the Cincinnati Childhood Allergy and Air Pollution Study, a high-risk birth cohort. A time weighted average exposure to traffic-related particles was determined by applying a land-use regression model to the homes, daycares, and other locations where children spent time from birth through age 36 months. Indoor levels of endotoxin were measured from dust samples collected prior to age 12 months. The relationship between dichotomized (< / 75th percentile) traffic-related particle and endotoxin exposure and persistent wheezing, controlling for potential covariates, was examined. Measurements and Main Results: Persistent wheezing at age 36 months was significantly associated with exposure to increased levels of traffic-related particles prior to age 12 months (OR = 1.75, 95%CI 1.07 – 2.87). Co-exposure to endotoxin had a synergistic effect with traffic exposure on persistent wheeze (OR = 5.85, 95% CI 1.89-18.13) after adjustment for significant covariates. Conclusions: The association between traffic-related particle exposure and persistent wheezing at age 36 months is modified by exposure to endotoxin. This finding supports prior toxicological studies demonstrating a synergistic production of ROS after co-exposure to DEP and endotoxin. The effect of early versus later exposure to traffic-related particles, however, remains to be studied due to the high correlation between exposure throughout the first three years of life.