This study evaluates serological responses to SARS-CoV-2 vaccination in individuals with inflammatory bowel disease (IBD). Serological responses to two, three, and four doses of a SARS-CoV-2 vaccine were assessed. We also aimed to determine the frequency of COVID-19 breakthrough infections (BTIs) in individuals with IBD during the Omicron wave and assess the association between antibodies and time to BTIs post-3rd dose vaccination. Five hundred fifty-nine adults with IBD who received at least one dose of a SARS-CoV-2 vaccine were enrolled. Serological responses were evaluated using the Abbott IgG II Quant assay and geometric mean titers (GMT) were calculated for each vaccine dose and serology time point. BTIs were assessed for nine months (Dec 1, 2021, to Sep 1, 2022) during the Omicron wave and confirmed through PCR, self-reported rapid antigen test, and/or positive nucleocapsid antibody levels. Cox proportional hazard models were evaluated to determine the effect of antibody concentration on the time from the 3rd dose vaccination to BTI after adjusting for demographic-, vaccine-, and treatment-related factors. In our cohort (n=559), 17.2 % were above 65 years of age, 53.1% were female, and 71.6% had Crohn’s diseaseSerological responses showed an increase in GMTs 1¬–8 weeks after each consecutive vaccine dose, wth the highest GMTs observed 1–8 weeks after the 2nd (4053 AU/mL), 3rd (12116 AU/mL), and 4th (14337 AU/mL) doses. GMTs decreased in the 8–16-week period after each dose, but levels remained stable beyond 16 weeks. Despite stability in antibody levels overtime, the cumulative incidence of Omicron-era BTI was 26.6% (95% CI: 22.4, 30.9%). Antibody concentration (anti-S) and neutralizing antibodies (NT50) were not associated with time from 3rd dose to breakthrough infection after adjusting for clinically relevant covariates (HR=0.70; 95% CI: 0.39, 1.24; p=0.22) and (HR=0.99; 95% CI: 0.99, 1.00; p=0.20). Overall, serological responses to SARS-CoV-2 vaccination increased after consecutive doses in those with IBD but decreased 8–16 weeks following each dose with titers stabilizing beyond 16 weeks. Cumulative incidence of BTI during the Omicron-era was high, and serum IgG and neutralizing antibodies were not predictive of BTI following 3rd dose vaccination.