Background: Lupus nephritis accounts for ∼1% of patients starting dialysis therapy. Treatment regimens combining cyclophosphamide with steroids preserve kidney function but have significant side effects. Newer immunosuppressive agents may have improved toxicity profiles. Study Design: Systematic review and random-effects meta-analysis, searching MEDLINE (1966 to April 2012), EMBASE (1988-2011), and the Cochrane Renal Group Specialised Register. Setting & Population: Patients with biopsy-proven proliferative lupus nephritis (classes III, IV, V+III, and V+IV). Selection Criteria: Randomized controlled trials. Intervention: Immunosuppressive treatment regimens used for induction and maintenance therapy of lupus nephritis. Outcomes: Mortality, renal remission and relapse, doubling of creatinine level, proteinuria, incidence of end-stage kidney disease, ovarian failure, alopecia, leukopenia, infections, diarrhea, vomiting, malignancy, and bladder toxicity. Results: 45 trials (2,559 participants) of induction therapy and 6 (514 participants) of maintenance therapy were included. In induction regimens comparing mycophenolate mofetil (MMF) with intravenous cyclophosphamide, there was no significant difference in mortality (7 studies, 710 patients; risk ratio [RR], 1.02; 95% CI, 0.52-1.98), incidence of end-stage kidney disease (3 studies, 231 patients; RR, 0.71; 95% CI, 0.27-1.84), complete renal remission (6 studies, 686 patients; RR, 1.39; 95% CI, 0.99-1.95), and renal relapse (1 study, 140 patients; RR, 0.97; 95% CI, 0.39-2.44). MMF-treated patients had significantly lower risks of ovarian failure (2 studies, 498 patients; RR, 0.15; 95% CI, 0.03-0.80) and alopecia (2 studies, 522 patients; RR, 0.22; 95% CI, 0.06-0.86). In maintenance therapy comparing azathioprine with MMF, the risk of renal relapse was significantly higher (3 studies, 371 patients; RR, 1.83; 95% CI, 1.24-2.71). Limitations: Heterogeneity in interventions and definitions of remission and lack of long-term outcome reporting. Conclusions: MMF is as effective as cyclophosphamide in achieving remission in lupus nephritis, but is safer, with a lower risk of ovarian failure. MMF is more effective than azathioprine in maintenance therapy for preventing relapse, with no difference in clinically important side effects.