We assessed the risk of second brain tumors in a cohort of patients with pituitary adenoma treated with conservative surgery and external beam radiotherapy. Four hundred and twenty-six patients (United Kingdom residents) with pituitary adenomas received radiotherapy at the Royal Marsden Hospital (RMH) between 1962 and 1994. They were followed up for 5749 person-years. The cumulative incidence of second intracranial tumors and systemic malignancy was compared with population incidence rates through the Thames Cancer Registry and the National Health Service Central Register (previously OPCS) to record death and the potential causes. Eleven patients developed a second brain tumor, including five meningiomas, four high grade astrocytomas, one meningeal sarcoma, and one primitive neuroectodermal tumor. The cumulative risk of second brain tumors was 2.0% [95% confidence interval (CI), 0.9–4.4%] at 10 yr and 2.4% (95% CI, 1.2–5.0%) at 20 yr, measured from the date of radiotherapy. The relative risk of second brain tumor compared with the incidence in the normal population was 10.5 (95% CI, 4.3–16.7). The relative risk was 7.0 for neuroepithelial and 24.3 for meningeal tumors. The relative risks were 24.2 (95% CI, 4.8–43.5), 2.9 (95% CI, 0–8.5), and 28.6 (95% CI, 0.6–56.6) during the intervals 5–9, 10–19, and more than 20 yr after radiotherapy (four cases occurred >20 yr after treatment). There was no evidence of excess risk of second systemic malignancy. An additional 10-yr update confirmed our previous report of an increased risk of second brain tumors in patients with pituitary adenoma treated with surgery and radiotherapy. The 2.4% risk at 20 yr remains low and should not preclude the use of radiotherapy as an effective treatment option. However, an increased risk of second brain tumors continues beyond 20 and 30 yr after treatment.