Preterm infants have smaller cerebral and cerebellar volumes at term compared with term born infants. Perinatal factors leading to the reduction in volumes are not well known. IL-6 -174 and -572 Genotypes partly regulate individual immunologic responses and have also been connected with deviant neurologic development in preterm infants. Our hypothesis was that IL-6 -174 and -572 genetic polymorphisms are associated with brain lesions and regional brain volumes in very low birth weight or in very preterm infants. DNA was genotyped for IL-6 -174 and -572 polymorphisms (GG/GC/CC). Study infants (n = 175) were categorized into three Groups according to the most pathologic brain finding ill ultrasound examinations until term. The brain MRI performed at term was analyzed for regional brain volumes. Analyzed IL-6 genotypes did not show statistically significant association with structural brain lesions. However, IL-6 -174 CC and -572 GG genotypes associated with reduced volume of one brain region, the combined Volume of basal ganglia and thalami, both in univariate and in multivariate analyses (p = 0.009, 0.009, respectively). The association of IL-6 -174 and -572 genetic polymorphisms with smaller Volumes in deep Gray matter provides us new ways to understand the processes leading to neurologic impairments in preterm infants. (Pediatr Res 65: 90-96, 2009)