HIV‐infected patients have a higher risk of developing cutaneous reactions to drugs than the general population. Severe cutaneous adverse reactions (SCARs) are not uncommon in patients taking antiretroviral therapy (HAART]. To evaluate HLA class I and II allele frequencies in HIV patients on HAART who develop SCARs due to nevirapine (NVP] or efavirenz (EFZ] containing regime and compare this genotype composition with HAART tolerant patients and healthy organ donors. A case‐control study for 4 years was conducted with four subsets of patients hailing from north‐east India:Cohort 1‐ HIV seropositive patients who developed SCARs due to EFZ (n = 8];Cohort 2 ‐ HIV seropositive patients who developed SCARs due to NVP (n = 15]; Cohort 3 ‐HIV seropositive NVP/EFZ‐tolerant patients (n = 18]; Cohort 4 ‐ Healthy HIV seronegative organ donors (n = 169].Cohort 3 & 4 acted as control‐group. These patients were genotyped for the HLA‐A, HLA‐B, HLA‐C, HLA‐DRB1, HLA‐DQB1, and HLA‐DPB1 by a sequence‐based HLA typing method. HLA‐DRB1*03:01 allele revealed a significant association with EFZ regimen‐induced SCARs in 62.5% patients compared with only 5.56% observed in HAART‐tolerant patients and 4.14% in healthy organ. HLA‐B*3505was found to be significantly associated with NVP induced SCARs. We found significant novel association of HLA‐DRB1*03:01 with EFZ induced SCARs in North‐East Indian HIV patients. Thus, HLA‐DRB*03:01 may be useful as a genetic marker to avoid EFZ induced serious cutaneous rashes. The molecular HLA characterization of these alleles may provide a novel insight into the immunological basis of the antiretroviral drug reactions.