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 longterm survival (72% vs 29%, P <.005) and fewer hospitalizations (0.24/patient‐years vs 0.89/patient‐years, P <.d001). Azathioprine therapy in 19 of 42 patients with a good prognosis was associated with fewer hospitalizations (.02/patient‐years vs.17/patient‐years, P <.05), but no decrease in maintenance prednisone requirement. Progression from a good to a poor prognosis was less frequent (1 of 20 vs 11 of 34, P <.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.