Purpose: To study the effect of combined use of prednisone and immunosuppressive therapy for systemic lupus erythematosus (SLE), and its impact on the incidence of adverse reactions.Methods: In total, 90 SLE patients treated in Longhui People's Hospital between January 2019 and January 2020 were included in this study, and assigned to receive either prednisone (control group) or immunosuppressive therapy and prednisone (study group) via the sealed envelope method. Outcome measures include immunoglobulin measured by enzyme-linked immunosorbent assay (ELISA), complement component 3 (C3) and C4 determined by immunoturbidimetric method, inflammatory factors such as INF-α, IL-10, and IL-6 levels, and the incidence of drug reactions.Results: After treatment, the treatment group had higher levels of immunoglobulin indices and C3 and C4 levels than the control group (p < 0.05). There were lower serum inflammatory factor levels in the treatment group than in the control group (p < 0.05). Prednisone and immunosuppressive therapy resulted in higher treatment effectiveness and lower SLEDAI scores, versus prednisone alone (p < 0.05).Conclusion: Prednisone and immunosuppressive therapy for SLE is safe, enhances treatment effectiveness, and improves clinical indicators in the patients. However, further trials are required prior to its application in clinical practice.