OBJECTIVES: To quantify the incidence of adverse events (AEs), identify discontinuation rates due to AEs, and determine the cost and resource use associated with AEs from azathioprine (AZA), cyclophosphamide (CYC), mycophenolate mofetil (MMF), methotrexate (MTX), and cyclosporine (CsA) in patients with systemic lupus erythematosus (SLE).  METHODS: A systematic review of English-language, MEDLINE- and EMBASE-indexed literature published between January 1980 and September 2011 was conducted using terms related to SLE, AEs, discontinuation, resource use and costs. RESULTS: This review identified 38 publications reporting the burden of AEs related to AZA, CYC, MMF, MTX or CsA.  The incidence of AEs ranged from 42.8% to 97.3%.  Common AEs included infections, gastrointestinal AEs and amenorrhea. In direct comparisons, AZA was associated with more hematological cytopenias than MMF (26.9% vs. 3.8%, respectively) based on one study.  CYC was associated with more infections than MMF (40-77% vs. 12.5-32%, respectively) or AZA (17-77% vs. 11-29%, respectively), and it was also related to more gynecological toxicities than MMF (32-36% vs. 3.6-6%, respectively) or AZA (32-71% vs. 8-18%, respectively). However, other studies reported no difference in AEs associated with CYC compared to either AZA or MMF, or with AZA compared to CsA. Discontinuation rates due to AEs were 0–17% in short-term randomized controlled trials (RCTs), 2.3–44.4% in long-term RCTs, and 1.9–21.8% in observational studies. The rate of hospitalized infections was similar between patients taking MMF and AZA (1 day per patient-year in each group), but higher for those taking CYC (10 days per patient-year).  No studies reported costs associated with AEs. CONCLUSIONS: The incidence of AEs associated with SLE immunosuppresants was consistently high as reported in the SLE literature, while discontinuation due to these AEs widely varied. Studies describing costs and resource use associated with these AEs were sparse and warrant further study.