Background: Previous literature revealed that cancer patients undergoing radiotherapy commonly experience physical and psychological symptom distress. Except lack of medical information, inadequate communication with physicians also affected patients' willingness and preparation toward radiotherapy. The prognosis consequently becomes worse. Objective: This study aimed to evaluate the change in symptom distress in cancer patients after radiotherapy and its predisposing factors. Methods: A longitudinal design was conducted on 164 cancer patients who underwent radiotherapy at a medical center in southern Taiwan. The structured questionnaire included sections on demographics, medical conditions, and a symptom distress scale. Results: Of the cancer patients, 35.9% reported an increase in the overall figures of symptom distress after radiotherapy, whereas 32.2% experienced a decrease. Cancer patients 20 to 39 years old or who received radiotherapy on the head and neck reported the greatest increase in bleeding and the overall figure of symptom distress. Patients after radiotherapy on the head and neck experienced significant increase in bowel disturbance. Conclusions: Radiotherapy did not necessarily increase symptom distress in all patients. The development of bleeding and the overall figure of symptom distress were closely related to younger age and site of radiotherapy. Implications for Practice: For those cancer patients 20 to 39 years old or who received radiotherapy on the head and neck, nurses may strengthen health education before radiotherapy and pay more attention after radiotherapy, especially in bleeding distress, and remind their families of the correct steps for nursing a wound after radiotherapy and the harmful effects of wound odor on patients' interpersonal relations.