Fifty-three patients with locally recurrent or persistent nasopharyngeal carcinoma were re-treated with megavoltage radiation therapy at The University of Texas M.D. Anderson Cancer Center from 1954 through 1989. The time from initial treatment to re-treatment ranged from 2 to 189 months (median 33 months). Documented local disease was confined to the nasopharynx in 27 patients (Group 1), while in the other 26 patients there was local spread beyond the nasopharynx (Group 2). At the time of re-treatment, nodal disease was present in 27 of the 53 cases. Forty-two patients were re-treated with external beam therapy alone and 11 with a component of brachytherapy. Re-treatment doses specified at the nasopharyngeal vault ranged from 27.5 to 99 Gy (median 57 Gy), and total cumulative dose ranged from 80 to 160 Gy (median 112 Gy). Overall 5-year actuarial local control (LC), disease-free survival (DFS), and survival rates were 35%, 18%, and 21%, respectively. Patients with Group 1 disease did better than those with Group 2 disease in terms of 5-year survival, 32% versus 9% (p = 0.01) and 5-year DFS, 23% versus 12% (p = 0.002). Nodal status at the time of re-treatment did not predict for LC or survival. The 5-year survival of patients with lymphoepitheliomas was 28% compared with 13% for patients with squamous cell carcinomas (p = 0.04). Eight patients developed severe complications from re-treatment, of which five involving the brain (two), spinal cord (one), and lower cranial nerves (two) were fatal. The incidence of severe complications was related to the total cumulative dose of external beam irradiation: 4% for patients receiving doses less-than-or-equal-to 100 Gy compared with 39% for those patients who received doses > 100 Gy (p = 0.066). Beginning in 1977, a combination of external beam therapy (20 to 30 Gy) and intracavitary cesium (40 to 50 Gy surface dose) was used in selected cases: 9 of the 53 patients were re-treated with this combination. Of these, 7 achieved LC with a follow-up of 7 to 102 months and none sustained a severe complication. Five-year actuarial LC, DFS, and survival in this group were 67%, 44% and 60% respectively.