Specific mutations of the TNF-alpha (TNF-alpha) and Lymphotoxin-alpha (LT-alpha) genes are correlated to the outcome of patients during serious infections. This study aimed at correlating these polymorphisms to lethal infections during childhood acute lymphoblastic leukemia (ALL). A matched case-control study of 34 patients who died due to infections during ALL treatment and 68 ALL patients without lethal infections was performed. Genomic DNA was isolated from blood smears and specific fragments including the polymorphic site of each gene were amplified. In the total study population, 23/102 (22.5%) of the children carried at least two variant alleles (high-producer haplotype). The variant genotypes were equally distributed between cases and controls [relative risk (RR) 1.17 (CI 0.33-2.22, P = 0.752)]. With regard to infective organisms, no statistically significant differences could be detected between the groups for bacterial infections [RR 1.59 (CI 0.56-4.50), P 0.379]. Patients with a LT-alpha (10.5 kb/5.5 kb; 5.5 kb/5.5 kb) haplotype, however, seemed to have a significant higher risk of attracting a lethal infection during induction/consolidation chemotherapy (RR 2.98, CI 0.98-9.01, P = 0.05). These results support a role of specific genetic polymorphisms on lethal infections during induction chemotherapy of ALL treatment.