Background Intravenous (IV) cyclophosphamide has been first-line treatment for inducing disease remission in lupus nephritis. The comparative efficacy and toxicity of newer agents such as mycophenolate mofetil (MMF) and calcineurin inhibitors are uncertain. Study Design Network meta-analysis. Setting & Population Patients with proliferative lupus nephritis. Selection Criteria for Studies Randomized trials of immunosuppression to induce or maintain disease remission. Interventions IV cyclophosphamide, oral cyclophosphamide, MMF, calcineurin inhibitor, plasma exchange, rituximab, or azathioprine, alone or in combination. Outcomes Complete remission, end-stage kidney disease, all-cause mortality, doubling of serum creatinine level, relapse, and adverse events. Results 53 studies involving 4,222 participants were eligible. Induction and maintenance treatments were administered for 12 (IQR, 6-84) and 25 (IQR, 12-48) months, respectively. There was no evidence of different effects between therapies on all-cause mortality, doubling of serum creatinine level, or end-stage kidney disease. Compared to IV cyclophosphamide, the most effective treatments to induce remission in moderate- to high-quality evidence were combined MMF and calcineurin inhibitor therapy, calcineurin inhibitors, and MMF (ORs were 2.69 [95% CI, 1.74-4.16], 1.86 [95% CI, 1.05-3.30], and 1.54 [95% CI, 1.04-2.30], respectively). MMF was significantly less likely than IV cyclophosphamide to cause alopecia (OR, 0.21; 95% CI, 0.12-0.36), and MMF combined with calcineurin inhibitor therapy was less likely to cause ovarian failure (OR, 0.25; 95% CI, 0.07-0.93). Regimens generally had similar odds of major infection. MMF was the most effective strategy to maintain remission. Limitations Outcome definitions not standardized, short duration of follow-up, and possible confounding by previous or subsequent therapy. Conclusions Evidence for induction therapy for lupus nephritis is inconclusive based on treatment effects on all-cause mortality, doubling of serum creatinine level, and end-stage kidney disease. MMF, calcineurin inhibitors, or their combination were most effective for inducing remission compared to IV cyclophosphamide, while conferring similar or lower treatment toxicity. MMF was the most effective maintenance therapy.