OBJECTIVE This study sought to continue research on psychosocial interventions for patients being treated with radiation therapy across multiple centers and to replicate positive findings of a single-center study of patients being treated with chemotherapy. The primary objective of this study was to determine if a stress management intervention was effective in improving quality of life and decreasing psychological distress in patients undergoing radiotherapy for cancer. METHODS A total of 310 patients about to begin radiotherapy treatment were randomly assigned to receive usual care only or self-administered stress management training. Quality-of-life assessments occurred at baseline and for 3 weeks after the beginning of radiotherapy treatment. RESULTS Overall, patients assigned to receive stress management training did not report significantly less psychological distress on the Medical Outcomes Study 36-Item Short Form (SF-36) Mental Component Summary Scale than did those assigned to usual care. When divided into subgroups based on the SF-36 Mental Component Summary Scale scores immediately after their first radiotherapy treatment, patients with above-average levels of psychological distress (scores < or = 50) who were randomly assigned to the intervention condition reported significant improvement in their distress compared with those assigned to usual care only on the SF-36 Mental Health Subscale and the Center for Epidemiologic Studies Depression Scale. CONCLUSIONS This study found that self-administered stress management training is effective only in those radiotherapy patients with initially higher levels of psychological distress. Additional research should examine the benefits of stress management training targeted specifically to patients experiencing heightened distress.