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Objective: Evaluate the efficacy and safety of guselkumab, an interleukin (IL)-23 inhibitor, in a Phase 2, multicentre, randomized, double-blind, placebo-controlled study of patients with active lupus nephritis (LN)., Methods: Adults (18-75 years) with active LN (Class III-IV proliferative nephritis [kidney biopsy] and urine protein-to-creatinine ratio [UPCR)] of ≥ 1 mg/mg despite standard-of-care therapy) were randomized (1:1; planned sample = 60) to receive intravenous infusions of guselkumab 400 mg or placebo at Weeks 0, 4, and 8, then subcutaneous injections (guselkumab 200 mg or placebo) at Week12 and every 4 weeks through Week48 in addition to their background therapy. The primary end point was achievement of ≥ 50% decrease in proteinuria from baseline at Week24. Major secondary endpoints (Week24) were achievement of complete renal response (CRR), sustained reduction in steroid dose (≤10 mg/day prednisone/equivalent) from Weeks 16-24, UPCR <0.5 mg/mg; <0.75 mg/mg, time to achieving CRR, and time to treatment failure. Safety was assessed through end-of-study., Results: Following enrolment challenges (COVID-19 pandemic; Ukraine/Russia crisis), the sponsor terminated the study early; 33 participants were randomized (placebo, n = 16; guselkumab, n = 17). At Week24, 56.3% (9/16) in the placebo group and 35.3% (6/17) in the guselkumab group achieved the primary end point. No apparent differences were observed in the secondary endpoints. Through end-of-study, 75% of placebo patients and 71% of guselkumab patients reported ≥1 adverse event; most were mild-to-moderate severity., Conclusion: Guselkumab+background therapy did not demonstrate superior reduction in proteinuria vs placebo+background in this small cohort of patients with active LN. Safety results were consistent with the known safety profile of guselkumab., Trial Registration: clinicaltrials.gov: NCT04376827., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Rheumatology.)