BACKGROUND: Recurrence of pituitary adenoma after Gamma Knife radiosurgery (GKRS) occurs in around 10% of cases. This study aims to evaluate the effectiveness and safety of repeat GKRS in pituitary adenoma patients who had tumor recurrence after the first GKRS. METHODS: This retrospective study included 38 consecutive patients who received a second GKRS treatment for pituitary adenoma at the same institute from 1994 to 2023. The primary study endpoint was tumor growth control. Safety assessment included neurological, visual, and endocrine function. RESULTS: The median radiological follow-up was 71.5 months (IQR, 21.7-124 months). Nine patients (23.7%) had recurrence of disease. The 5-year and 10-year progression-free survival rates were 75.2% (95% CI, 58.4-92.0%) and 61.7% (95% CI, 39.3-84.1%), respectively. Adjusted Cox analysis showed that hormone-secreting adenoma (HR 6.82
95% CI, 1.42-32.68
P 0.02), having received another surgical procedure before repeat GKRS (HR 10.63
95% CI, 1.77-63.85
P 0.01), and the interval between the first and the second GKRS (HR 0.97
95% CI, 0.95-0.99
P 0.01) were independently associated with the risk of tumor recurrence. No serious side effects occurred after repeat GKRS treatment, except one case of transient diplopia and trigeminal neuralgia. New thyroid, gonadal, and adrenal deficit developed in 10.5%, 7.1%, and 18.7% of patients, respectively. CONCLUSION: Repeat GKRS for regrowth of a pituitary adenoma can stop tumor progression in most patients. No specific safety concerns emerged. Repeat GKRS can be included among the few therapeutic options available after failure of a first GKRS.