BACKGROUND Normalization of IGF-I in patients with acromegaly is associated with a decrease in mortality. Pegvisomant may be more effective in lowering IGF-I than octreotide. METHODS The efficacy and safety of pegvisomant and octreotide long-acting release (LAR) were compared in 118 patients with acromegaly in this 52-week, multicenter, open-label, randomized study. The primary endpoint was IGF-I normalization at week 52. Secondary endpoints included mean changes from baseline in IGF-I, IGF binding protein 3, acromegaly signs and symptom scores, ring size, acromegaly quality of life questionnaire scores, and safety. RESULTS Fifty-six patients received pegvisomant and 57 received octreotide LAR. IGF-I normalized in 51% of pegvisomant patients and 34% treated with octreotide LAR (p=0.09, ns). Patients with baseline IGF-I > or = 2x upper limit of normal had a higher rate of IGF-I normalization with pegvisomant vs octreotide LAR (p=0.05). Among the patients who did not achieve a normalized IGF-I, pegvisomant-treated patients were more likely to be receiving < 30 mg of study drug (71% vs 16%). Treatment-related adverse events were mild-to-moderate in both groups. Mean fasting glucose decreased in diabetic and non-diabetic patients on pegvisomant whereas octreotide LAR was associated with an increase at week 52 (p=0.005 and p=0.003 between groups, respectively). Mean change in tumor volume during treatment was similar between groups. CONCLUSIONS Pegvisomant and octreotide LAR were equally effective in normalizing IGF-I in the overall population, and pegvisomant was more effective in patients with higher baseline IGF-I levels. Pegvisomant had a more favorable effect on parameters of glycemic control.