BACKGROUND: Circulating levels of tumor necrosis factor (TNF) and lymphotoxin-alpha (LT-alpha) have been associated with outcome in solid and hematologic malignancies. Within the TNF gene and the LT-alpha gene, polymorphisms have been identified at nucleotide positions -308 and +252, respectively. The variant alleles for TNF are designated TNF1 and TNF2, the ones for LT-alpha LT-alpha (10.5 kb) and LT-alpha (5.5 kb). Of interest, TNF2 and LT-alpha (5.5 kb) were shown to be associated with higher TNF and LT-alpha plasma levels than their counterparts. In the present study, we investigated the associations of the above mentioned polymorphisms with risk of relapse in childhood acute lymphoblastic leukemia (ALL) treated according to Berlin-Frankfurt-Münster (BFM) protocols. METHODS: Matched case-control study of 64 relapsed and 64 successfully treated non-relapsed childhood B-cell precursor ALL patients of standard and intermediate risk for treatment failure. RESULTS: The odds ratio (OR) for the combined category of TNF1/TNF2 and TNF2/TNF2 genotypes in comparison to the TNF1/TNF1 genotype was 1.17 (95 % confidence interval (CI) = 0.53 - 2.56, P = 0.697). The ORs for the LT-alpha (10.5 kb/5.5 kb) and the LT-alpha (5.5 kb/5.5 kb) genotypes with reference to the LT-alpha (10.5 kb/10.5 kb) genotype were 2.17 (95 % CI = 0.84 - 5.58, P = 0.107) and 0.5 (95 % CI = 0.09 - 2.66, P = 0.418), respectively. CONCLUSIONS: Our results do not suggest a major role of the investigated genetic polymorphisms with regard to risk of relapse in standard- and intermediate-risk childhood B-cell precursor ALL treated according to BFM protocols.