Introduction. Systemic lupus erythematosus (SLE) is a complex chronic autoimmune disease with diverse clinical manifestations. Treatment stabilization is crucial for optimal disease control, but the consistency of immunosuppressive therapy may be affected by non-ideal conditions, including drug unavailability or adverse effects. This study aimed to assess the association between unplanned immunosuppressant switching and increased disease activity in SLE patients. Methods. A retrospective cohort study of SLE patients meeting the inclusion criteria, whose disease activity was evaluated using the MEX-SLEDAI score during immunosuppressant substitution. Participants were grouped into an exposed group undergoing unplanned immunosuppressant switching due to drug unavailability and a comparison group continuing maintenance therapy without switching. Disease activity was assessed using the MEX-SLEDAI score during follow-up. Results. A total of 213 SLE patients were included; 45 patients (21.1%) experienced increased disease activity. Unplanned immunosuppressant substitution was significantly associated with increased disease activity (RR 2.06; 95% CI 1.18–3.60; p=0.011), and remained significant after adjustment for confounders (aRR 1.82; 95% CI 1.05–3.15; p=0.034). Subgroup analysis showed most flares occurred within the first three months after substitution, and mycophenolate-containing replacement regimens were associated with a lower risk of increased disease activity (p=0.025). Conclusions. Unplanned immunosuppressant substitution is associated with increased disease activity in SLE patients. Close monitoring following switching is essential to maintain disease stability.