BACKGROUND: Reduced life expectancy has been shown in patients with hypopituitarism, mainly caused by cardiovascular diseases. A major cause of hypopituitarism is pituitary adenomas, and radiotherapy may be employed as a treatment modality to reduce the post-operative regrowth rate of these tumours. Recently, we showed that in patients with craniopharyngiomas, tumour regrowth foreshadowed a fourfold risk increase for death. For patients with pituitary adenomas, the impact of regrowth on life expectancy is, however, not known. OBJECTIVE: To assess the impact of a reoperation due to a regrowth of a pituitary macroadenoma on mortality, taking into account other candidate prognostic factors. DESIGN AND PATIENTS: In 281 patients with operated and irradiated macroadenomas, excluding acromegaly and Cushing's disease, 35 patients had a regrowth (median follow-up 16.6 years). Possible risk factors for tumour regrowth were investigated by Cox regression models. RESULTS: For tumour regrowth, age, calendar time at primary surgery, gender and extension of tumour growth had no statistically significant impact. For younger patients, the proportion of regrowths was higher, but after age-stratified Cox regression analysis only regrowth was shown to have a significant impact on mortality, with a more than doubled mortality risk for patients with tumour regrowth as compared with the non-regrowing tumour patients (hazard ratio=2.24, P<0.001). This finding was corroborated by cohort analyses using the general population as an external comparison group. CONCLUSION: Among patients with irradiated pituitary macroadenomas, excluding acromegaly and Cushing's disease, a doubled mortality rate was observed for those reoperated for tumour regrowth as compared with patients with non-regrowing tumours.