Background: Vaccination is a promising strategy to protect vulnerable groups like inflammatory bowel disease (IBD) patients against COVID-19 and associated severe outcomes. COVID-19 vaccine clinical trials excluded IBD patients taking infliximab with azathioprine or 6-mercaptopurine (infliximab combination). Therefore, we sought to evaluate serologic responses to COVID-19 vaccination with the mRNA vaccine, BNT162b2, in patients with IBD receiving infliximab combination therapy compared with healthy participants. Method: This was a multicenter prospective study. Patients with IBD were recruited at the time of attendance at infusion center between 1 August 2021, and 15 September 2021. Our primary outcome were the concentrations of SARS-CoV-2 antibodies 4–10 weeks after vaccination with two doses of BNT162b2 vaccine in patients with IBD taking infliximab combination therapy (study group) compared with a healthy participants group (control group). Both study and control groups were matched for age, sex, and time-since-last-vaccine-dose using optimal pair-matching method. Results: In total, 116 participants were recruited in the study, 58 patients in the study group and 58 in the control group. Median (IQR) IgG concentrations were lower in the study group (99 BAU/mL (40, 177)) than the control group (139 BAU/mL (120, 188)) following vaccination (p = 0.0032). Neutralizing antibodies were also lower in the study group compared with the control group (64% (23, 94) vs. 91% (85, 94), p < 0.001). The median IgA levels in the study group were also significantly lower when compared with the control group (6 U/mL (3, 34) vs. 13 U/mL (7, 30), p = 0.0097). In the study group, the percentages of patients who achieved positive IgG, neutralizing antibody and IgA levels were 81%, 75%, and 40%, respectively. In the control group, all participants (100%) had positive IgG and neutralizing antibody levels while 62% had positive IgA levels. Conclusion: In patients with IBD receiving infliximab combination therapy, SARS-CoV2 IgG, IgA, and neutralizing antibody levels after BNT162b2 vaccination were lower compared with healthy participants. However, most patients treated with infliximab combination therapy seroconverted after two doses of the vaccine.