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Background: Otosclerosis is a common form of hearing impairment among Western-Eurasian adults. The cause of otosclerosis remains unknown. Autoimmune reaction against the otic capsule has been suggested as a possible aetiologic factor in otosclerosis. Aim: The present study is the first report to evaluate the relationship between class I major histocompatibility complex (MHC) genes (HLA-A, HLA-B and HLA-Cw) and genetic susceptibility to otosclerosis in Tunisian patients. Subjects and methods: Fifty unrelated Tunisian patients exhibiting clinical otosclerosis were typed for HLA-A, HLA-B and HLA-Cw antigens and compared with 100 ethnically-matched healthy controls. Results: Increased frequencies of HLA-A*03 (OR = 4.16, Pc < 0.043), HLA-B*35 (OR = 2.76, Pc < 0.043) and HLA-Cw*03 (OR = 4.57, Pc < 0.043) antigens were found in the patients with otosclerosis compared with healthy controls. Individuals with HLA-A*30 (OR = 0.25, Pc < 0.043), HLA-B*51 (OR = 0.11, Pc < 0.043), HLA-Cw*16 (OR = 0.08, Pc < 0.043) and Cw*06 (OR = 0.32, Pc < 0.043) antigens have a protective effect against otosclerosis. Conclusions: In conclusion, the data suggest that a variation in class I HLA antigens could be a genetic factor involved in susceptibility to otosclerosis in the Tunisian population. [ABSTRACT FROM AUTHOR]