In the present study, HLA associations among the cohort of 171 severe P. falciparum malaria patients were compared with that of 101 normal sex, age and ethnically matched control samples. All these individuals lived in Mumbai in an area of low and seasonal P. falciparum transmission. HLA A, B, DRB1 and DQB1 antigens were serologically (A and B) and molecularly (DRB and DQB) determined using isolated lymphocytes and genomic DNA following the microlymphocytotoxicity assay and PCR-SSP techniques. Significant differences were observed between patients with malaria and controls in the following groups of alleles: A3, B27, B49, DRB1*04, and DRB1*0809 were increased, while A19, A34, B18, B37, and DQB1*0203 were decreased. HLA B49 and DRB1*0809 were found to be positively associated with the complicated severe malaria patients (OR = 13.88; p < 0.0001). HLA A19, B5 and B13 were protective in patients with high parasite index (> 2%). These observations revealed the importance of ethnic background, which has to be taken into consideration while developing an ideal malaria vaccine. Further, when compared to HLA associations of other world populations the present study indicates the relative importance of different HLA alleles that may vary in different populations.