Objective The multinational, phase 3, double‐blind, placebo‐controlled TULIP‐SC trial evaluated the efficacy and safety of subcutaneous anifrolumab in adults who have moderate‐to‐severe SLE activity, despite receiving standard therapy. Methods Adults with SLE received subcutaneous anifrolumab 120 mg or placebo once weekly for 52 weeks (1:1 randomization). Only the primary endpoint (treatment difference in BILAG‐based Composite Lupus Assessment [BICLA] response at 52 weeks) was formally tested in a pre‐planned interim analysis; key secondary and other endpoints were tested in the full analysis. Results At the interim analysis (220 patients, anifrolumab: n=109; placebo: n=111), the primary endpoint was met (anifrolumab vs placebo: 59.4% vs 43.9%; BICLA response difference [95% confidence interval]=15.5% [2.3–28.6%], p =0.0211). The full analysis included 367 patients (anifrolumab: n=184; placebo: n=183). Versus placebo, more patients treated with anifrolumab attained a BICLA response whilst maintaining low/reduced oral glucocorticoid doses through Week 52 (56.2% vs 34.0%; difference=22.3% [12.3−32.2] p <0.0001), and the time to first sustained BICLA response was reduced (Hazard ratio=2.2 [1.5−3.2]; p <0.0001). Treatment differences in Week 52 DORIS remission and Low Lupus Disease Activity State attainment rates favored anifrolumab over placebo (14.2% [5.6−22.8%], p =0.0012, and 14.1% [4.6−23.6%], p =0.0038). The frequencies of serious adverse events were 11.9% with anifrolumab and 10.4% with placebo; the frequencies of herpes zoster were 3.8% and 1.1%, respectively. Conclusion Consistent with the well‐established profile of intravenous anifrolumab, subcutaneous anifrolumab demonstrated significant, clinically meaningful treatment benefits when added to standard therapy, and an acceptable safety profile in patients with moderate to severe SLE.