Rheumatic diseases affect the musculoskeletal system and may also compromise internal organs. The immunosuppressive treatments commonly used in these conditions can weaken the immune system, raising concerns about the efficacy of immunizations, particularly against SARS-CoV-2. This observational and analytical study evaluated the humoral immune response in patients with rheumatic diseases who were vaccinated with a fourth dose of the SARS-CoV-2 vaccine in comparison with a control group and the effect prior COVID-19 infection. The results showed that individuals with a history of COVID-19 infection developed significantly higher levels of neutralizing antibody titers, indicating a stronger immune response. Moreover, the response on the Wuhan strain elicited a more robust humoral response than the Omicron strain in both immunocompromised patients and healthy controls. These findings highlight the impact of previous viral exposure on the effectiveness of immunization in rheumatology patients.