One hundred ten patients with systemic lupus erythematosus (SLE) were classified into two groups, patients with central nervous system (CNS) or severe renal disease (usually associated with a poor prognosis) and patients without these manifestations, to define criteria for azathioprine therapy. Fifty-four of 68 patients with a poor prognosis received azathioprine. Azathioprine-treated patients showed improved long-term survival (72% vs 29%, P less than .005) and fewer hospitalizations (0.24/patient-years vs 0.89/patient-years, P less than .001). Azathioprine therapy in 19 of 42 patients with a good prognosis was associated with fewer hospitalizations (.02/patient-years vs .17/patient-years, P less than .05), but no decrease in maintenace prednisone requirement. Progression from a good to a poor prognosis was less frequent (1 of 20 vs 11 of 34, P = less than .05) among azathioprine-treated patients. Toxicity of azathioprine was minimal. Azathioprine therapy is indicated in patients with CNS or severe renal disease, and in patients whose prognosis was good with frequent hospitalizations or a maintenance prednisone requirement greater than 15 mg/day.