To assess the effect of road traffic exhaust on the risk of childhood leukemia, we carried out a population-based case-control study in the Province of Varese, northern Italy, covered by a population-based cancer registry. All 120 incident cases from 1978–97 were included in the study. Four controls per case, matched by age and gender, were sampled from population files. As index of exposure to traffic exhaust we estimated the annual mean concentration of benzene outside the home using a Gaussian diffusion model. This model uses traffic density (vehicles/day) on nearby main roads, distance between roads and residence, and information on vehicle emissions and weather conditions to estimate benzene concentration. Compared to children whose homes was not exposed to road traffic emissions (<0.1 μg/m3 of benzene as estimated by the model), the risk of childhood leukemia was significantly higher (relative risk [RR] = 3.91; 95% confidence interval [CI] = 1.36–11.27) for heavily exposed children (over 10 μg/m3 estimated annual average). For the intermediate exposure group (0.1–10 μg/m3) the relative risk was 1.51 (95% CI = 0.91–2.51). These data, considered with other available evidence, suggest that motor traffic emissions can be involved in the etiology of childhood leukemia. © 2003 Wiley-Liss, Inc.