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Although childhood cancer is a leading cause of childhood mortality in the US, evidence regarding the etiology is lacking. The goal of this study was to evaluate the association between benzene, a known carcinogen, and childhood acute leukemia.We conducted a case-control study including cases diagnosed with acute leukemia between 1997 and 2012 (n = 307) from the Oklahoma Central Cancer Registry and controls matched on week of birth from birth certificates (n = 1013). We used conditional logistic regression to evaluate the association between benzene, measured with the 2005 National-Scale Air Toxics Assessment (NATA) at census tract of the birth residence, and childhood acute leukemia.We observed no differences in benzene exposure overall between cases and controls. However, when stratified by year of birth, cases born from 2005 to 2010 had a three–fold increased unadjusted odds of elevated exposure compared to controls born in this same time period (4th Quartile OR: 3.53, 95% CI: 1.35, 9.27). Furthermore, the estimates for children with acute myeloid leukemia (AML) were stronger than those with acute lymphoid leukemia, though not statistically significant.While we did not observe an association between benzene and childhood leukemia overall, our results suggest that acute leukemia is associated with increased benzene exposure among more recent births, and children with AML may have increased benzene exposure at birth. Using the NATA estimates allowed us to assess a specific pollutant at the census tract level, providing an advantage over monitor or point source data. Our study, however, cannot rule out the possibility that benzene may be a marker of other traffic-related exposures and temporal misclassification may explain the lack of an association among earlier births.Benzene is a suspected, but uncertain, risk factor for childhood acute leukemia.Enhanced benzene estimates account for activity and multiple sources of exposure.Potential dose-response relation revealed for benzene and acute myeloid leukemia.