OBJECTIVE Acromegaly that has not been cured by microsurgery is usually treated with fractionated radiotherapy; however, it is not possible to repeat such a treatment with effective radiation doses if it should fail. The authors pose the question: Can stereotactic radiosurgery be used as an effective, alternative method for retreatment by irradiation? METHODS A retrospective study of 12 patients was performed to compare patients treated with Gamma Knife surgery (GKS) after initial, failed radiotherapy and 37 patients treated with GKS only. The mean dose for the initial fractionated radiotherapy was 44.6 Gy (range 40-54 Gy). The mean maximum GKS dose was 45.1 Gy (range 27-50 Gy) in the pretreated group and 49.5 Gy (range 25-70 Gy) in the group undergoing GKS alone. The mean interval between the two treatments was 10.6 years (range 3-20.6 years). The age-related insulin-like growth factor-I (IGF-I), assessed at 3-month intervals, was the main follow-up parameter. An IGF-I normalization rate of more than 80% was achieved in both patient groups; however, the latency of endocrinological normalization was longer in the patients who had undergone failed fractionated radiotherapy (median time to cure 35.4 months compared with 13.5 months). CONCLUSIONS Treatment with GKS is successful in patients with acromegaly even after failed fractionated radiotherapy; GKS represents a therapeutic tool in patients with no therapeutic options life-long octreotide. It must be noted that the incidence of neurological complications is higher (p < 0.01, 2 x 2 crosstab). The remaining dose fraction after previous fractionated radiotherapy appears to be approximately 50%. Maintenance of other endocrinological functions may be better after GKS alone; however, the difference is not significant.