Background: Immunogenicity to tumour necrosis factor inhibitors is a significant clinical problem leading to treatment failure and adverse events. The study aimed to assess human leukocyte antigen (HLA) associations with anti‐drug antibody (ADAb) formation to infliximab. Methods: Immune‐mediated inflammatory disease patients on infliximab therapy (n = 612) were included. Neutralising ADAb were assessed with a drug‐sensitive assay. Next generation sequencing‐based HLA typing was performed. Results: Overall, 147 (24%) patients developed ADAb. Conditional analyses indicated HLA‐DQB1 (p = 1.4 × 10−6) as a primary risk locus. Highest risk of ADAb was seen when carrying at least one of the HLA‐DQ2 haplotypes; DQB1*02:01–DQA1*05:01 or DQB1*02:02–DQA1*02:01 (OR 3.18, 95% CI 2.15–4.69 and p = 5.9 × 10−9). Results were consistent across diseases and when adjusting for concomitant immunomodulator. Computational predictions indicated that these HLA‐DQ2 haplotypes bind to peptide motifs from infliximab light chain. Conclusion: A genome‐wide significant association between two HLA‐DQ2 haplotypes and the risk of ADAb formation to infliximab was identified, suggesting that HLA‐DQ2 testing may facilitate personalised treatment decisions. [ABSTRACT FROM AUTHOR]