Objective: This study aimed to investigate the association between exposure to environmental chemicals and the risk of childhood acute lymphocytic leukemia(cALL). Methods: A case-controlled study was conducted in Shenzhen Children's Hospital, China from January 2015 to January 2016. The cases were selected from the section of Hematology and Oncology, and the controls were selected from Orthopedics by 1∶2 matching of cases according to sex and age. A questionnaire including population data and chemical exposure characteristics was conducted on the children's parents, and urine and EDTA-blood were collected from the children. Then, we quantitatively measured the internal dose of formaldehyde(i.e., formaldehyde-human serum albumin)by enzyme-linked immunosorbent assay and the doses of metabolites benzene, toluene, and xylene(i.e., trans-muconic acid, hippuric acid, and methylhippuric acid)by high-performance liquid chromatography. Logistic regression models were used to analyze the relationships between exposure factors measured from children and their parents and cALL. Results: In the study, 71 cases(average age: 6.08±3.61 years), and 142 controls(average age: 5.91±3.57 years)were assessed; there were no differences in general demographics between two groups. The self-reported results showed that living in a home that had been painted in the past 10 years(OR=4.39, 95% CI: 1.87-10.31), maternal chemical exposure during pregnancy(OR=11.78, 95% CI: 1.65-83.88), paternal diesel or gasoline exposure(OR=8.15, 95% CI: 2.68-24.83), paternal dye exposure(OR=7.77, 95% CI: 1.52-39.67)and trash burning near the child's residence(OR=6.08, 95% CI: 1.17-31.66)were associated with increased risk of cALL. The positive detection rates of only benzene metabolites were significantly higher in cases(40/44)than controls(81/111)(χ²=5.92, P=0.021). The median formaldehyde and benzene concentrations in cases(32.120 pg/ml, 2.505 μg/gCr)were significantly higher than those in controls(18.705 pg/ml, 0.672 μg/gCr; Z values:-1.98 and-3.95, P values: 0.047 and<0.001, respectively). Multiple logistic regression analysis showed that benzene exposure(OR=1.09, 95% CI: 1.00-1.19), home painting in the past 10 years(OR=3.56, 95% CI: 1.20-10.53)and paternal diesel or gasoline exposure(OR= 3.75, 95% CI: 1.06-13.22)were associated with increased risk of cALL. Conclusion: A variety of environmental chemistry factors, such as benzene exposure, increase the risk of cALL, and further studies are warranted to explore their specific roles.