The management of patients with acromegaly, who are inadequately controlled after surgery and medical therapy with first-generation somatostatin receptor ligands (SRLs), is challenging. Treatment with a second-generation SRL, pasireotide long-acting release (LAR), or treatment with the growth hormone antagonist, pegvisomant (PEG), as a monotherapy may be considered. However, combined medical therapy remains an important option. With the development of oral octreotide capsule (OOC) and a reduced burden on patients (no injections), additional combination therapies may be also possible. This chapter focuses on the efficacy and safety of first-generation SRL-PEG combination therapy. Also highlighted are pasireotide LAR-PEG studies and SRL-cabergoline and cabergoline-PEG combination medical treatments. Somatostatin receptor ligand-PEG combination treatment normalizes insulin-like growth factor-1 (IGF-1) in approximately two thirds of patients. Treatment efficacy continues despite individual drug dosing or frequency reduction in those patients who are responsive. Pegvisomant may also negate the adverse effects of first-generation SRLs on glycemic control. Somatostatin receptor ligand- PEG combination treatment may also be considered in those patients who benefit from symptom relief with SRLs despite inadequate IGF-1 reduction during SRL monotherapy and those patients with large remnant tumor volumes. Pasireotide LAR-PEG has been shown to be effective in patients with uncontrolled acromegaly, tumor growth, or persistent symptoms despite high doses of first-generation SRLs-PEG. It has been shown that PEG has a sparing effect of pasireotide LAR. The risk of hyperglycemia is, however, significantly higher than with first-generation SRLs. As such a pasireotide LAR-PEG combination option may not be suitable for patients with poorly controlled diabetes mellitus (DM). A combination of SRLs-cabergoline is generally well-tolerated and may be most effective in patients with mildly elevated IGF-1. Data on PEG-cabergoline combination treatments are limited. However, PEG-cabergoline may be an option in cases of SRL intolerance or in cases of poorly controlled DM. Individualization of patient medical therapy (mono or combination) remains key.