Context: Pasireotide (SOM230) is a novel multireceptor ligand somatostatin analog with affinity for somatostatin receptor subtypes sst1–3 and sst5. Because most GH-secreting pituitary adenomas express sst2 and sst5, pasireotide has the potential to be more effective than the sst2-preferential somatostatin analogs octreotide and lanreotide. Objective: Our objective was to evaluate the efficacy and safety of three different doses of pasireotide in patients with acromegaly. Design: We conducted a phase II, randomized, multicenter, open-label, three-way, crossover study. Patients: Sixty patients with acromegaly, defined by a 2-h five-point mean GH level higher than 5 μg/liter, lack of suppression of GH to less than 1 μg/liter after oral glucose tolerance test, and elevated IGF-I for age- and sex-matched controls. Patients could have had previous surgery, radiotherapy, and/or medical therapy or no previous treatment. Intervention: After treatment with octreotide 100 μg sc three times daily for 28 d, each patient received pasireotide 200, 400, and 600 μg sc twice daily in random order for 28 d. Main Outcome Measure: A biochemical response was defined as a reduction in GH to no more than 2.5 μg/liter and normalization of IGF-I to age- and sex-matched controls. Results: After 4 wk of octreotide, 9% of patients achieved a biochemical response. After 4 wk of pasireotide 200–600 μg sc bid, 19% of patients achieved a biochemical response, which increased to 27% after 3 months of pasireotide; 39% of patients had a more than 20% reduction in pituitary tumor volume. Pasireotide was generally well tolerated. Conclusions: Pasireotide is a promising treatment for acromegaly. Larger studies of longer duration evaluating the efficacy and safety of pasireotide in patients with acromegaly are ongoing. Results from this phase II study demonstrate that pasireotide is a promising novel treatment for patients with acromegaly.