BACKGROUND: The COVID-19 pandemic has led to widespread infection, with a significant subset of patients developing persistent symptoms known as Long COVID. Understanding the genetic factors influencing Long COVID susceptibility and severity is crucial for development of targeted interventions. OBJECTIVE: This study aimed to evaluate the impact of HLA alleles, KIR receptors, and their interactions on the development of Long COVID in patients from southeastern Spain having contracted COVID-19 during the early 2020 pandemic wave. METHODS: A cross-sectional prospective study enrolled 153 COVID-19 patients. Three months post-infection, HLA-A, -B, -C, KIR genotyping and immunological variables were analyzed using serum and blood samples. Long COVID was diagnosed three years post- infection based on persistent symptoms. RESULTS: Among the participants, 71 developed Long COVID. HLA-A*03 was less frequent in Long COVID compared to non-Long COVID patients (10.7 % vs. 30.5 %, p = 0.001). Patients with HLA-A*03 had a higher percentage of CD8 CONCLUSION: HLA-A*03 may play a protective role against Long COVID, potentially through enhanced immune responses involving CD8