Objective: To investigate long-term safety and tolerability of anifrolumab, a human monoclonal antibody to the type I interferon (IFN) receptor subunit 1, in patients with moderate-to-severe systemic lupus erythematosus (SLE). Methods: This 3-year, multinational, open-label extension study included adult patients who completed treatment (48 weeks of anifrolumab or placebo; 12-week follow-up) in the MUSE phase IIb randomized controlled trial (RCT). Patients initially received 1,000 mg of anifrolumab intravenously every 4 weeks, which was reduced to 300 mg every 4 weeks based on the benefit/risk profile established in the MUSE trial. Adverse events (AEs) were assessed monthly. Exploratory end points included the SLE Disease Activity Index 2000 (SLEDAI-2K), Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI), pharmacodynamics, and health-related quality of life (HRQoL). Results: Of the 246 patients who completed the RCT, 218 (88.6%) enrolled in the open-label extension study, of which 139 (63.8%) completed 3 years of treatment. Approximately 69.7% of patients reported ≥1 AE during the first year of open-label extension treatment. Frequency and patterns of serious AEs and AEs of special interest over 3 years were consistent with those reported for 1 year of treatment in the RCT. Few patients (6.9%) discontinued treatment due to AEs. No new safety signals were identified. Improvement in the SLEDAI-2K was sustained over 3 years. SDI and Short Form 36 health survey scores remained stable. Neutralization of type I IFN gene signatures was maintained in the IFN-high population, and C3, C4, and anti–double-stranded DNA showed trends toward sustained improvement. Conclusion: Long-term anifrolumab treatment demonstrates an acceptable safety profile with sustained improvement in SLE disease activity, HRQoL, and serologic measures.