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Objectives and design To further elucidate the effects of rare systemic autoimmune rheumatic diseases (SARD) and their treatment on antibody development after vaccination against SARS-CoV-2, we compared patients with and without immunosuppressive therapy to healthy controls in an observational cohort study.Participants and setting We enrolled 52 patients with SARD and 72 healthy subjects in a prospective, observational study at the Medical University of Vienna and measured the humoral response 6 months after two mRNA vaccinations and 2–6 weeks after a third dose.Results Patients with vasculitis showed significantly (p=0.02) lower antibody titres 6 months after vaccination (median 247 BAU/mL, IQR [185–437]), as compared with healthy controls (median 514 BAU/mL, [185–437], IQR 323; 928, vasculitis patients: 247, IQR [185; 437], p<0.05). Patients receiving 2–3 immunomodulatory medications showed significantly lower antibody levels. Of note, all patients with SARD, even those without immunomodulatory medication, developed lower antibody levels after the third dose compared with healthy controls (median 22 630, IQR [16 945; 43 200] in HC, 9510 IQR [3866; 14 215] in patients without immunosuppressive treatment (p<0.001), 7780 IQR [2203; 15 645] in patients receiving a single immunomodulatory drug (p<0.0001) and 14 320 IQR [2415; 35 400] in patients receiving combination therapy (p=0.081)).Conclusions Patients with SARD displayed lower antibody development after booster vaccination, even if antibody levels after two immunisations were comparable to healthy controls. Our data may be limited due to sample size, but it provides pointers for a more individualised, antibody-titre-oriented approach and earlier booster vaccination in patients with SARD.