BACKGROUND: Subacute sclerosing panencephalitis (SSPE) is a rare but fatal neurological syndrome resulting from persistent measles virus infection in the central nervous system. Despite the availability of a measles vaccine, SSPE continues to pose a significant health burden, and immunogenetic risk factors remain unclear. We aimed to study the role of the interleukin 12 (IL-12)/interferon-gamma (IFN-γ) axis, known for it's significance in antiviral defense, in the development of SSPE. METHODS: This cross-sectional case-control study recruited consecutive age and sex-matched SSPE cases (n = 51) and controls (n = 51). Gene expressions were quantified for IL-12B, IFNG, IL-12RB1, STAT4, IFNGR1, IFNGR2, STAT1, IRF8, and ISG15 genes using quantitative realtime PCR. Additionally, plasma levels of IL-12p40, IL-12p70, and IFN-γ were measured using the multiplex suspension array platform. Furthermore, single nucleotide polymorphisms (SNPs) in IL-12B, IL-12RB1, IFNG, IFNGR1, IFNGR2, and ISG15 genes were examined using TaqMan SNP genotyping assays. Statistical analyses compared gene expressions, cytokine levels, and alleles and genotypes frequencies between SSPE patients and controls. RESULTS: Significant alterations in the expression of key IL-12 pathway-related genes were observed in SSPE patients compared to controls, including lower STAT4 (p = 0.0445) and higher IFNGR1 (p = 0.0005) and IRF8 (p = 0.0229). Elevated plasma levels of IL-12p70 (p = 0.0025) and IFN-γ (p = 0.0381) were also observed in SSPE patients. Additionally, associations with SSPE were found for the rs3212227 SNP in IL-12B (p = 0.048), the rs1059293 SNP in IFNGR2 (p = 0.052), and the rs1921 SNP in ISG15 (p = 0.054) genes. Notably, gene-gene interactions among these genes exhibited associations with SSPE. CONCLUSION: This study provides novel insights into the dysregulation of the IL-12/IFN-γ immune axis in SSPE and underscores the complex interplay between host genetics and viral infection in disease pathogenesis.