Introduction: We conducted a prospective study to investigate possible influence of genetic polymorphisms of the interleukin genes in the clinical severity, 6 months outcome and hemorrhagic events in patients with TBI. In particular, we tested the IL-1β(-511C/T), IL-1β(+3953C/T), IL-1α(-889C/T), IL-1RA (VNTR), IL-2(+114G/T), IL-2(-384T/G) and IL-6(-174G/C) polymorphisms. Patient-Methods: 365 (women=60 [16.4%]) prospectively recruited patients with TBI were evaluated. Initial neurological status and six-month outcome were assessed by means of the Glasgow Coma Score and Glasgow Outcome Scale respectively. Based on computed tomography findings at admission patients were stratified according to the presence and type of haemorrhagic event. DNA was extracted using the salting out method, while SNPs genotypes were determined using standard PCR/RFLP methods The Hardy-Weinberg equilibrium was assessed by means of the Fisher’s exact test. For comparisons between categorical variables we used the χ2 test. Multivariable logistic regression analysis was used to control for possible confounding factors. Analysis for dominant recessive and allele contrast models of inheritance was performed. Linkage disequilibrium between SNPs was examined and haplotype estimation was performed by an expectation-maximization algorithm. Control for multiple comparisons was performed using Bonferroni’s correction for 7 polymorphisms. The level of significance (p) was equal to 0.007 (0.05/7=0.007). Results: No statistically significant difference was found for IL-1β(-511C/T), IL-1β(+3953C/T), IL-1α(-889C/T), IL-2 (-384T/G) and IL-6(-174G/C) polymorphisms. Allele T of IL-2(+114G/T) polymorphism was associated with more severe clinical presentation at admission(p=0.002). Compared to noncarriers, IL-1RA allele 2 carriers had 4.5 times higher odds of having cerebral hemorrhages after TBI (p=0.004). Haplotype analysis of IL-1 SNPs (IL-1α -889C/T, IL-1β +3953C/T, IL-1β -511C/T, IL-1RA VNTR) revealed that haplotype IV (1-1-2-2) was associated with increased risk for more severe clinical presentation at admission (p=0.0005) and hemorrhagic events (p=0.0058). Haplotype VIII (2-2-2-1) was associated with higher likelihood for milder clinical presentation at admission (p=2.64*10-5), while haplotype VI (2-1-1-1) was linked to unfavourable 6month outcome (p=0.0004). Haplotype analysis of IL-2 SNPs (IL-2 +114G/T, IL-2 -384T/G) revealed that haplotype II (2-1) was associated with increased risk for more severe clinical presentation at admission (p=0.00087). Conclusions: Our study provides evidence of an implication of interleukins genetic polymorphisms in the clinical presentation at admission, 6 months outcome and hemorrhagic events of TBI patients. However, further studies are needed to confirm these associations and investigate underlying pathogenetic mechanisms.