SummaryA sudden upsurge of fever cases with joint pain was observed in the outpatient department, Community Health Centre, Rangat during July–August 2010 in Rangat Middle Andaman, India. The aetiological agent responsible for the outbreak was identified as chikungunya virus (CHIKV), by using RT‐PCR and IgM ELISA. The study investigated the association of polymorphisms in the human leucocyte antigen class II genes with susceptibility or protection against CHIKV. One hundred and one patients with clinical features suggestive of CHIKV infection and 104 healthy subjects were included in the study. DNA was extracted and typed for HLA‐DRB1 and DQB1 alleles. Based on the amino acid sequences of HLA‐DQB1 retrieved from the IMGT/HLA database, critical amino acid differences in the specific peptide‐binding pockets of HLA‐DQB1 molecules were investigated. The frequencies of HLA‐DRB1 alleles were not significantly different, whereas lower frequency of HLA‐DQB1*03:03 was observed in CHIKV patients compared with the control population [P = 0·001, corrected P = 0·024; odds ratio (OR) = 0, 95% confidence interval (95% CI) 0·0–0·331; Peto's OR = 0·1317, 95% CI 0·0428–0·405). Significantly lower frequency of glutamic acid at position 86 of peptide‐binding pocket 1 coding HLA‐DQB1 genotypes was observed in CHIKV patients compared with healthy controls (P = 0·004, OR = 0·307, 95% CI 0·125–0·707). Computational binding predictions of CD4 epitopes of CHIKV by NetMHCII revealed that HLA‐DQ molecules are known to bind more CHIKV peptides than HLA‐DRB1 molecules. The results suggest that HLA‐DQB1 alleles and critical amino acid differences in the peptide‐binding pockets of HLA‐DQB1 alleles might have role in influencing infection and pathogenesis of CHIKV.