Abstract Background Air pollution is associated with asthma exacerbations. We examined the associations of exposure to ambient particulate matter (PM₁₀) and nitrogen dioxide (NO₂) with the risk of wheezing in preschool children, and assessed whether these associations were modified by tobacco smoke exposure. Methods This study was embedded in the Generation R Study, a population-based prospective cohort study among 4,634 children. PM₁₀ and NO₂ levels were estimated for the home addresses using dispersion modeling. Annual parental reports of wheezing until the age of 3 years and fetal and infant tobacco smoke exposure was obtained by questionnaires. Results Average annual PM₁₀ or NO₂ exposure levels per year were not associated with wheezing in the same year. Longitudinal analyses revealed non-significant tendencies towards positive associations of PM₁₀ or NO₂ exposure levels with wheezing during the first 3 years of life (overall odds ratios (95% confidence interval): 1.21 (0.79, 1.87) and 1.06 (0.92, 1.22)) per 10 μg/m³ increase PM₁₀ and NO₂, respectively). Stratified analyses showed that the associations were stronger and only significant among children who were exposed to both fetal and infant tobacco smoke (overall odds ratios 4.54 (1.17, 17.65) and 1.85 (1.15, 2.96)) per 10 μg/m³ increase PM₁₀ and NO₂, respectively (p-value for interactions <0.05). Conclusions Our results suggest that long term exposure to traffic-related air pollutants is associated with increased risks of wheezing in children exposed to tobacco smoke in fetal life and infancy. Smoke exposure in early life might lead to increased vulnerability of the lungs to air pollution.