In patients with inflammatory bowel disease (IBD), use of the anti-TNF agent infliximab has been associated with reduced serological responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. 6,935 patients with IBD were recruited from 92 hospitals across the UK in the CLARITY study, and antibody responses to SARS-CoV-2 infection were examined in patients treated with infliximab or vedolizumab (a reference cohort). Rates of symptomatic and proven SARS-CoV-2 infection were similar between the groups, but seroprevalence was lower in the infliximab group than in the vedolizumab group (3.4% versus 6.0%, P < 0.0001). Seroconversion and the magnitude of anti-SARS-CoV-2 reactivity were also attenuated in the infliximab group. Moreover, serological responses in infliximab-treated patients were further diminished by concomitant immunodulator use (thiopurines or methotrexate; only 37% of these individuals had detectable SARS-CoV-2 antibodies); both infliximab and immunomodulator use were independently associated with lower seropositivity.