BACKGROUND: Severe COVID-19 is characterized by dysregulated host immune responses and immune-mediated endothelial injury, culminating in microvascular dysfunction and systemic inflammation. Endothelial lipase (EL), encoded by the LIPG gene, regulates endothelial lipid metabolism and inflammatory signaling pathways that influence immune-endothelial interactions. Despite its relevance to vascular immunopathology, the immunogenetic contribution of LIPG promoter variants to immune-driven endothelial dysfunction in COVID-19 remains poorly defined. METHODS: We performed a case-control study including 151 RT-PCR-confirmed COVID-19 patients stratified according to disease severity and 152 healthy controls. Genotyping of the LIPG -384A/C (rs3813082) promoter variant was carried out using polymerase chain reaction-based allelic discrimination. Associations between genotype and disease severity were evaluated alongside inflammatory and immune-related parameters, including serum ferritin and total leukocyte count. In silico analyses were conducted to assess the impact of the promoter variant on transcription factor binding sites involved in immune and inflammatory regulation. RESULTS: The LIPG -384C allele was significantly associated with an increased risk of severe COVID-19 and a heightened inflammatory profile. Individuals carrying the risk allele demonstrated significantly elevated ferritin levels and leukocyte counts, indicative of amplified systemic immune activation. Computational functional annotation revealed that the -384A/C substitution modifies transcription factor binding motifs linked to inflammatory and immune-responsive pathways, supporting a mechanistic role for this variant in regulating endothelial immune signaling. CONCLUSION: This study identifies the LIPG -384A/C promoter variant as a novel immunogenetic determinant of COVID-19 severity, potentially mediating disease progression through modulation of immune-driven endothelial inflammation. Our findings underscore the critical role of host immunogenetic factors at the immune-endothelial interface in shaping inflammatory responses and clinical outcomes in COVID-19, providing insight into vascular immunopathology and host susceptibility.