Total body irradiation (TBI) produces prolonged immunosuppression with rare side effects. We studied 12 thymectomized patients affected with chronic generalized severe myasthenia gravis. All patients had been totally or partially refractory to prolonged oral treatment with immunosuppressive drugs, and most had contraindications for these drugs. Low-dose (1.8- to 2.3-Gy total dose) TBI was administered in single, 0.1-Gy doses, two to three times per week. TBI was well tolerated and was associated with objective clinical improvement in six patients, lasting more than 2 years in five. In addition, TBI produced a long-lasting lymphopenia with a pronounced decrease of T CD4+ lymphocytes; T CD8+ lymphocytes were almost unchanged over the 2 years of the study. CD16+ and CD20+ lymphocytes, after an initial decrease, increased above baseline. TBI was also associated with decreased anti-AChR antibody titer. The decrease of lymphocyte count and of anti-AChR antibody titer was more pronounced in the patients who improved, suggesting that lymphopenia and immunosuppression may have contributed to clinical improvement.