Eleven patients with rheumatoid arthritis that had been refractory to conventional drug therapy were treated with total lymphoid irradiation (TLI). Followup continued for 6 months in 9 patients, 12 months in 6 patients, and 24 months in 3 patients. At 6 and 12 months post-TLI, a significant improvement in clinical disease activity was demonstrated. Side effects noted during TLI included fatigue, nausea, diarrhea, and vomiting. One patient died of cardiorespiratory arrest, 2 patients died of kidney failure secondary to generalized amyloidosis, and 1 patient died of septic shock secondary to a multilocular septic arthritis. One patient experienced 2 episodes of septic arthritis; 2 patients manifested delayed wound healing. Immunologic assessments showed consistent lymphopenia in all patients. T lymphocyte subsets decreased after TLI, and showed a transient increase at 6 months post-TLI. The suppressed mitogen responsiveness, which was noted 2 months after irradiation, was found to increase almost to the pre-TLI levels at 12 months. The observed increase in morbidity and mortality after TLI is evidence that discourages the use of this therapeutic technique, at least in its present form.