It is difficult to predict outcome in neonates that experience perinatal hypoxic ischaemia. Morbidity and mortality may be affected by genetic factors that augment inflammatory and coagulative responses. This prospective study analysed the effects of proinflammatory cytokine gene polymorphisms (tumour necrosis factor-alpha [TNFA] 308G>A and interleukin-6 [IL6] 174G>C) and prothrombotic factor gene mutations (prothrombin G20210A, factor V Leiden G1691A and methylenetetrahydrofolate reductase [MTHFR] C677T) on the early neurological prognosis in 40 term hypoxic ischaemic encephalopathic neonates. There were significant relationships for Sarnat and Sarnat staging with electroencephalographic findings, transfontanelle ultrasound (US) results, early neonatal outcome and neurological morbidity. Genetic mutations in the prothrombotic proteins, the TNFA 308G>A polymorphism and the cerebrospinal fluid levels of TNF-alpha protein were not related to clinical stage, electroencephalography, transfontanelle US or neurological status at discharge or at postnatal months 6 and 12. The IL6 174GC genotype demonstrated a protective role, being significantly correlated with normal electroencephalography, transfontanelle US and normal neurological findings at discharge. In conclusion, the IL6 174GC gene polymorphism seems to play a role in determining the risk and/or severity of perinatal cerebral injury.