Somatostatin analogs (SSAs) represent the mainstay of therapy in acromegaly. One of the potential disadvantages is the expected need to maintain therapy indefinitely in previously non-irradiated patients. The aim of this multicenter prospective open trial was to evaluate the likelihood of successful discontinuation of SSA therapy in well-controlled acromegalic patients who fulfilled very strict criteria: two or more years of treatment with the long-acting SSA octreotide LAR (OCT-LAR), a stable dose and injections interval every 4 weeks or longer for the previous year, GH levels <2.5 ng/ml and normal IGF-1 levels for age, a tumor remnant <10 mm, no history of radiotherapy, and no use of cabergoline or pegvisomant over the previous 6 months. Disease recurrence was defined as an increase of IGF-1 to levels above 1.2-fold the upper limit of normal (ULN). Out of 220 patients, 20 patients (12 women and 8 men; mean age, 48.1 ± 10.3 years; age range, 27-64) treated for 2.74 ± 0.64 years (range, 2.0-4.4) were included in this prospective study and OCT-LAR therapy was stopped. Four patients (20 %) remained without clinical and biochemical/neuroradiological evidence of disease recurrence after 12-18 months of follow-up. Sixteen patients (80 %) relapsed biochemically within 9 months after drug withdrawal and restarted OCT-LAR at the same previous dose. Compared to recurring subjects, non-recurring patients had significantly lower mean IGF-1 (× ULN) levels but there were some overlapping values in both groups. No other characteristic could be identified as a predictor of successful OCT-LAR discontinuation. Our findings demonstrated that OCT-LAR withdrawal, though rare, is possible in well-selected acromegalic patients treated for at least 2 years and considered optimally controlled in hormonal and neuroradiological terms.