Intravenous (i.v.) cyclophosphamide has been the treatment of choice for diffuse proliferative glomerulonephritis (DPGN) in patients with systemic lupus erythematosus (SLE). However, there is little guidance in the medical literature about what to do when this therapy fails. Mycophenolate mofetil (MMF), a new immunosuppressive agent, has been used successfully in patients with solid organ transplants and rheumatoid arthritis. We report two patients with diffuse proliferative glomerulonephritis who responded favorably to MMF therapy after i.v. cyclophosphamide failed.