Background: Treatment for acromegaly patients with long-acting somatotropin release-inhibiting factor (LA-SRIF) often does not result in complete normalization of IGF-1. Addition of pegvisomant (PEGV), a GH receptor antagonist, could improve this; however, the literature has not described long-term follow-up. Objective: To assess long-term efficacy and safety of this combined treatment in the largest current single-center cohort of patients, from 2004-2013. Design: Acromegaly patients were treated for at least 6 months with a high-dose LA-SRIF. To patients with persistently elevated IGF-1 levels (>1.2 x upper limit of normal) or poor quality of life, PEGV was added as one weekly injection. Results: The patients (n = 141) were treated with PEGV and LA-SRIFs for a median period of 4.9 years (range, 0.5-9.2). Efficacy, defined as the lowest measured IGF-1 level during treatment, was 97.0%. The median PEGV dose to achieve this efficacy was 80 mg weekly (interquartile range, 60-120 mg). Combination treatment-related adverse events were recorded in 26 subjects (18.4%). Pituitary tumor size increase was observed in one patient. Injection-site reactions were observed in four subjects. In 19 patients (13.5%), transiently elevated liver transaminases of more than three times the upper limit of normal were observed, of which 83% occurred within the first year of combination treatment. Eight patients died, at a mean age of 71 years; none of them were considered treatment-related. Conclusions: The combination treatment with LA-SRIFs and PEGV was effective in 97% of the patients, it appears to be a safe medical treatment and it reduces the required dose of PEGV.