Objective: To evaluate the humoral response to and effectiveness of SARS-CoV-2 vaccination in patients with systemic lupus erythematosus in a multicenter cohort design. Methods: Data for this analysis were obtained from the Study of Safety, Effectiveness and Duration of Immunity after Vaccination against SARS-CoV-2 in Patients with Immune-Mediated Inflammatory Diseases (SAFER), a prospective, multicenter, phase IV, real-world study conducted across different regions of Brazil. Patients aged >18 years with systemic lupus erythematosus (SLE) who received any one of the SARS-CoV-2 vaccines approved by the Brazilian health regulatory agency (CoronaVac [Inactivated SARS-CoV-2 Vaccine], ChAdOx-1 [AstraZeneca], or BNT162b2 [Pfizer-BioNTech]) were included. Immunogenicity was assessed in pre- and post-vaccination blood samples, and patients were monitored in person and remotely for incident COVID-19 cases and their severity. Results: Two hundred and thirty-five patients with SLE who had completed their vaccination schedules (2 doses + booster dose) were included in this study. Most patients were female (89.3%) and had low disease activity or were in remission (72.4%); the majority were also on some form of immunosuppressive therapy (58.1%). One hundred and sixteen patients received 2 doses of CoronaVac followed by 1 dose of BNT162b2 (Pfizer-BioNTech) vaccine, 87 received 2 doses of ChAdOx1-S (AstraZeneca) followed by 1 dose of BNT162b2 (Pfizer-BioNTech) vaccine, and 32 received 3 doses of BNT162b2 (Pfizer-BioNTech) vaccine. Twenty-eight incident cases of COVID-19, none meeting severity criteria, were recorded in patients with respiratory symptoms after the second dose of a SARS-CoV-2 vaccine. Regarding immunogenicity, an increase in seroconversion rate was observed, with no difference between vaccination schedules, reaching 97.57% seropositivity after a booster dose. The increases in geometric mean IgG titers differed between the different vaccination schedules, being lowest for the CoronaVac-based schedule, but titers were similar after administration of a booster dose. Conclusion: In patients with SLE, SARS-CoV-2 vaccines are immunogenic and effective in reducing severe disease and hospitalization. Complete vaccination schedules including a booster dose were associated with induction of a greater humoral response, especially in patients initially immunized with an inactivated virus vaccine schedule and those with a suboptimal humoral response.