BACKGROUND AND OBJECTIVES: The adenosine pathway in drug-resistant epilepsy (DRE) due to hippocampal sclerosis (HS) is largely unexplored. The present study aims to provide new insights into the role of adenosine pathway in patients with DRE associated with HS (DRE-HS). METHODS: Quantitative polymerase chain reaction and immunohistochemistry were used to analyze 10 genes involved in adenosine pathway ( ADARB1 , ADK , NT5E , ADORA1 , C-FOS, C-MYC, CREB1, C-JUN, NF-kB1, and MAPK ) in surgically resected sclerosed hippocampi (n = 37) and compare their expressions with control hippocampi (n = 38) obtained from the autopsy. Expression analyses were also carried out in peripheral blood of 20 matched patients and 30 healthy controls. RESULTS: C-JUN , NT5E , C-FOS , ADARB1 , and ADORA1 were significantly upregulated in the hippocampus, whereas in blood, C-JUN , NT5E , C-FOS , and ADORA1 were significantly downregulated. ADARB1 , NF-kB1 , MAPK1, C-FOS, and CREB1 showed the reverse direction of expressions in post-surgery blood samples. On clinico-genetic analysis, MAPK1 and ADARB1 correlated with neuronal dispersion in the dentate gyrus ( P = 0.02 and 0.03, respectively) and C-JUN correlated with neuronal loss in CA1 ( P = 0.01) and CA4 ( P = 0.04) areas. In blood, MAPK1 , NF-kB1 , and C-FOS expressions correlated negatively with the age of onset of seizures ( P = 0.02, 0.03, and 0.03, respectively). In addition, ADARB1 expression correlated with neuronal loss in CA3 and CA4 areas ( P ≤ 0.001 and 0.04, respectively). CONCLUSION: Genes with similar expression patterns in the brain and peripheral blood are potential biomarkers in DRE-HS. Significant clinico-genetic correlations warrant further studies for developing novel therapeutic interventions.