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Background We lack predictors of response to biologics in the management of patients with inflammatory bowel disease (IBD). A recent study has shown a significant association between HLA-DQA1*05 carriers and the development of loss of response to anti-tumor necrosis factor (TNF) mediated by immunogenicity. Methods Retrospective single-center cohort study including IBD patients who had received anti-TNF therapy as a first biologic and whose HLA-DQA1*05 had been determined. Primary nonresponse and secondary failure (assessed by survival analysis) have been evaluated as well as safety outcomes. Results A total of 199 IBD patients (161 [81%] with Crohn’s disease and 38 [19%] with ulcerative colitis) were included. A total of 42.4% were HLA-DQA1*05 carriers and 60% received combination therapy at the start of anti-TNF treatment. Median follow-up was 24 (interquartile range, 11-66) months. No statistically significant differences were found in primary nonresponse to anti-TNF (89.3% vs 87.8%; P = .825), depending on HLA carriers and noncarriers. No differences in secondary loss of response according to HLA variant in any of the analyses performed (full cohort, according to IBD or anti-TNF type) were observed. Again, no differences were observed in patients treated with combination therapy. In terms of safety, no significant differences were found in the rate of infusion reactions or serious adverse events. Conclusion In our real-life cohort of IBD patients treated for the first time with anti-TNF, being an HLA-DQA1*05 carrier did not act as a predictor of response failure, either primary or secondary. The safety of anti-TNF treatment has also not been influenced by the variant. Lay Summary The HLA variant DQA1*05 has been identified as a risk factor for the development of antibodies to anti-tumor necrosis factor drugs. We observed that its presence has no impact on clinical outcomes, such as secondary loss of response. These data suggest that caution is required before making decisions based on this HLA variant.