Optimal biochemical control cannot be attained by long-acting somatostatin analog monotherapy in a large proportion of patients with acromegaly. Such therapy might result in increased mortality, poor control of signs and symptoms of disease and decreased quality of life. Combination treatment with somatostatin analogs and pegvisomant (a growth-hormone-receptor antagonist) is, however, highly effective at normalizing the level of insulin-like growth factor I in over 90% of patients and might also have a favorable effect on quality of life in those with biochemically controlled acromegaly. Moreover, whereas pegvisomant monotherapy does not lead to a decrease in the size of the pituitary tumor, combination therapy with somatostatin analogs results in a clinically relevant decrease in tumor size in about 20% of patients. The main adverse effects of combination treatment are transient elevations in the levels of transaminases, which occur in about 15% of patients, especially in those with diabetes mellitus. In this Review, we discuss the available data on the long-term efficacy and safety of somatostatin analog-pegvisomant combination treatment and its potential use in patients with acromegaly.