OBJECTIVE: To assess the antibody response to disease-modifying antirheumatic drug (DMARD) therapy after the first and second dose of the ChAdOx1nCov-19 (AstraZeneca (AZ)) and BNT162b (Pfizer) vaccines in patients with immune-mediated inflammatory disease (IMID) compared with controls and if withholding therapy following the first vaccination dose has any effect on seroconversion and SARS-CoV-2 antibody (Ab) levels. METHODS: A multicentre three-arm randomised controlled trial compared the immunogenicity of the Pfizer and AZ vaccines in adult patients on conventional synthetic (csDMARD), biologic (bDMARD) or targeted synthetic (tsDMARD) therapy for IMID (n=181) with a control group (n=59). Patients were randomised to continue or withhold DMARD therapy for 1-2 weeks post first dose vaccination only. Serum SARS-CoV-2 IgG detection (IgG ≥1.0 U/mL) and titres against the S1/S2 proteins were measured at baseline, 3-4 weeks post first vaccination and 4 weeks post second vaccination. RESULTS: AZ vaccination was given to 47.5%, 41.5% and 52.5% in the continue, withhold and control groups, respectively while Pfizer vaccination was given to 52.5%, 58.5% and 47.5% among the continue, withhold and control groups, respectively. Seroconversion rates following the first dose in the AZ and Pfizer groups were only 27.3% vs 79.2% (p=0.000) and 64.58% vs 100% (p=0.000), respectively in the IMID groups who continued therapy compared with the AZ and Pfizer controls, respectively. Withholding DMARD therapy following the first vaccination dose resulted in higher seroconversion to 67.7% and 84.1% in the AZ and Pfizer groups, respectively. Following the second AZ and Pfizer vaccinations when all DMARDs were continued, despite a slightly lower seroconversion rate (83.7% vs 100%, p=0.000 and 95.9% vs 100%, p=0.413), respectively, the mean SARS-CoV2 IgG Ab titres were not significantly different in the csDMARD and bDMARD groups compared with the controls regardless of hold while it was significantly lower in patients taking tsDMARD (12.88 vs 79.49 U/mL, p=0.000). CONCLUSIONS: Following the first vaccination dose, antibody responses were lower in IMID on DMARD therapy, however the final responses were excellent regardless of hold with the exception of the tsDMARD group where withholding therapy is recommended. At least 2 vaccinations are therefore recommended preferably with an messenger RNA vaccine. TRIAL REGISTRATION NUMBER: ANZCTR: 12621000661875.