Background: The genes encoding the human leukocyte antigens (HLAs; major histocompatibility complex [MHC]) have been considered candidate markers for periodontitis because they are involved in regulating immune responses. Several studies have examined this association, and despite the inconclusive results, the antigens HLA‐A9 and HLA‐B15 have been found to be consistently associated with the destructive forms of periodontitis in many populations. Ethnic factors are considered to be a major variable for evaluating the predisposition to the disease. The purpose of the present study was to: 1) assess the association of HLA‐A*9 and HLA‐B*15 with generalized aggressive periodontitis (GAgP) and 2) evaluate the role of these genetic risk factors in influencing the severity of GAgP in a South Indian population.Methods: Forty GAgP patients (cases) and 80 periodontally and systemically healthy subjects (controls) participated in this study. HLA‐A*9 and HLA‐B*15 typing was carried out using the polymerase chain reaction with sequence specific primers (PCR‐SSP)‐based molecular method.Results: HLA‐B*15 was a significant risk factor for GAgP and was positively correlated with the disease severity, whereas HLA‐A*9 had no association with the disease. The haplotype of HLA‐A*9:B*15 did not impart any additional risk for GAgP compared to that imparted by HLA‐B*15 alone.Conclusions: To our knowledge, this is the first report on HLA‐B*15 association with GAgP in an Indian population. The finding of HLA‐B*15 as a risk factor may have potential use in the future management of GAgP. The precise disease‐causing mechanism of this HLA disease association and whether this association is “causal” or “casual” need to be evaluated further.