The objective of the present study was to investigate the effects of octreotide long acting release (S-LAR) preparation on GH and IGF-1 serum concentrations and pituitary tumor size in patients with persistent and difficultly controlled acromegaly even after adjuvant irradiation and/or dopamine agonists. Thirty-three patients with active acromegaly (26 female and 7 male, mean age; 43.94 ± 14.01 SD years) were included in this study. Patients were evaluated at baseline and at 6, 12, 30 and 40 months for GH, IGF-1, and GH response to OGTT and biliary ultrasonography. Sella MRI was performed at initial and at 40 months. All patients received 20 mg S-LAR. Afterwards, the dosage was titrated to improve individual GH response and reduction of IGF-1 into normal ranges. Basal serum IGF-1 levels decreased from median: 530 μg/l [IQR: 420–600] to 340 μg/l [IQR: 230–460] at 6 months (p = 0.01), to 400 μg/l [IQR: 222.4–600] at 12 months (p = 0.48), to 396 μg/l [IQR: 318–468] at 30 months (p = 0.49), to 482 μg/l [308–580] at 40 months (p = 0.47). Nadir GH levels in OGTT fell from 2.70 ng/ml [IQR: 1.35–6.90] to 1.60 ng/ml [IQR: 0.36–4.10] at 6 months (p = 0.03), to 0.31 ng/ml [IQR: 0.18–0.65] at 12 months (p<0.0001), to 1.50 ng/ml [IQR: 0.83–4.00] at 30 months (p = 0.398) and to 0.89 ng/ml [IQR: 0.58–1.35] at 40 months (p<0.0001). Initially, pituitary adenoma volume was median: 1.18 ml [IQR: 0.08–3.50] and it shrank to 0.21 ml [IQR: 0–2.1] at 40 months (p = 0.08). Gallstones were detected in 12 patients and six of them underwent cholecystectomy. S-LAR is an effective treatment regimen in reducing GH and IGF-1 concentrations and as well as in shrinking tumor volume in persistent and difficultly controlled acromegalic patients.