Genetic polymorphisms in the promoter regions of FAS, FASL and CASP8 involved in the apoptotic signaling pathway are thought to be associated with susceptibility to cancer. We hypothesized that these functional genetic variants might be associated with the risk of childhood acute lymphoblastic leukemia (ALL). A case-control study in a Chinese population with 361 cases of ALL and 519 controls was performed to evaluate the association between FAS, FASL and CASP8 variants and risk of childhood ALL. Individuals with FAS - 1377AG had an odds ratio (OR) of 0.72 for the risk of ALL compared to - 1377GG and the variant FASL - 844CC was associated with a statistically significantly decreased risk of childhood ALL (OR = 0.38). Furthermore, combined genotypes with 5-8 protective alleles were associated with a significantly decreased risk of childhood ALL compared with those with 0-4 variants, and this decreased risk was more pronounced among the subgroups of age < 6 years, female, parental never-drinking status and never house-painting. Our results provide evidence that FAS-FASL-CASP8 polymorphisms contributed to a reduced risk of childhood ALL in our population. Larger studies are warranted to validate our findings.