Acromegaly is associated with impaired quality of life (QoL). We investigated the effects of biochemical control of acromegaly by growth hormone receptor antagonism vs somatostatin analog therapy on QoL. Cross-sectional. 116 subjects: n=55 receiving a somatostatin analog (SSA group); n=29 receiving pegvisomant (PEG group); n=32 active acromegaly on no medical therapy (ACTIVE group). Acromegaly QoL Questionnaire (AcroQoL), Rand 36-Item Short Form Survey (SF-36) and Gastrointestinal QoL Index (GIQLI); fasting glucose, insulin and IGF-1 levels (LC/MS, Quest Diagnostics). There were no group differences in mean age, BMI or sex [(whole cohort mean ± SD) age 52±14years, BMI 30±6kg/m2 , and male sex 38%]. Mean IGF-1 Z-scores were higher in ACTIVE (3.9±1.0) vs SSA and PEG, which did not differ from one another (0.5±0.7 and 0.5±0.7, P<.0001 vs ACTIVE). Eighty-three per cent of PEG previously received somatostatin analogs, which had been discontinued due to lack of efficacy (52%) or side effects (41%). There were no differences in the four QoL primary end-points (AcroQoL Global Score, SF-36 Physical Component Summary Score, SF-36 Mental Health Summary Score and GIQLI Global Score) between SSA and PEG. Higher HbA1c, BMI and IGF-1 Z-scores were associated with poorer QoL in several domains. Our data support a comparable QoL in patients receiving pegvisomant vs somatostatin analogs, despite the fact that the vast majority receiving pegvisomant did not respond to or were not able to tolerate somatostatin analogs.