Background <p>Air pollution, in particular due to traffic, is suspected of increasing the risk of childhood acute leukemia (AL), most of the evidence coming from epidemiological studies and literature reviews that focused on the time around diagnosis. Using data on the national scale, we tested the hypothesis that prenatal exposure to traffic-related air pollution increases the risk of childhood AL.</p> Methods <p>This case–control study included 581 cases of acute lymphoblastic leukemia (ALL) and 136 cases of acute myeloid leukemia (AML), registered in the French national registry of childhood cancer and born and diagnosed between 2010 and 2015, and 11,908 controls. Exposure indicators were evaluated at the addresses at birth and included major road length in 500&#xa0;m buffers, and modeled exposures of nitrogen dioxide (NO₂), fine particulate matter (PM_2.5) and black carbon (BC). Odds ratios (OR) and 95% confidence intervals (CI) were estimated using logistic regression models. Exposures were considered in categories using tertiles’ cut offs or continuously for increments of ½ interquartile range.</p> Results <p>Both ALL and AML risks increased with PM_2.5 exposure (OR ALL = 1.14, 95%CI = 1.08–1.20 and OR AML = 1.12, 95%CI = 1.00–1.25 for an increment of 2&#xa0;µg/m³, respectively). The risk of ALL was associated with BC exposure in urban units of &lt; 5,000&#xa0;inhabitants and of 5,000–99,999&#xa0;inhabitants (OR = 1.90, 95%CI = 1.22–2.97 and OR = 1.58, 95%CI = 1.16–2.17 for an increment of 0.5&#xa0;10^–5/m, respectively), and not in more urban municipalities. An elevated OR for AML was observed for NO₂ exposure (OR = 1.4, 95%CI = 0.9–2.1 for the highest <i>versus</i> lowest category). There was no association with the length of major roads.</p> Conclusion <p>The results support a role of exposure to air pollution at time of birth in the risk of childhood AL.</p>