Systemic infection is a major risk factor for the development of neonatal acute renal failure (ARF). We investigated whether genetic polymorphisms of tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, IL-6, and IL-10 genes leading to a more intense inflammatory response might predispose very low birth weight (VLBW) infants to the development of ARF in severe infection. The medical records of 92 VLBW newborns (birth weight under 1,500 g) with systemic infection were analyzed. ARF developed in 38 infants during the 1st postnatal week, while 54 neonates exhibited normal renal function. The variants of TNF-alpha, IL-1beta, IL-6, and IL-10 genes were determined from dried blood samples with polymerase chain reaction and restriction fragment length polymorphism methods. The allele frequencies did not differ in ARF and in non-ARF babies, while the (TNF-alpha /IL-6) AG/GC or AG/CC haplotypes were more often present in ARF (26% vs. 6%, P<0.01). The single presence of TNF-alpha, IL-1beta, IL-6, and IL-10 variants does not influence the development of ARF, but the constellation of TNF-alpha and IL-6 genetic variants is associated with ARF. We hypothesize that the simultaneous presence of these polymorphisms might lead to an enhanced inflammatory response in the kidneys in babies with infection.