Objective: The objective of the study was to assess whether weekly administration of 40 mg pegvisomant (PEG-V) improves quality of life (QoL) and metabolic parameters in acromegalic patients with normal age-adjusted IGF-I concentrations during long-acting somatostatin analog (SSA) treatment. Design: This was a prospective, investigator-initiated, double blind, placebo-controlled, crossover study. Twenty acromegalic subjects received either PEG-V or placebo for two consecutive treatment periods of 16 wk, separated by a washout period of 4 wk. Efficacy was assessed as change between baseline and end of each treatment period. QoL was assessed by the Acromegaly Quality of Life Questionnaire (AcroQoL) and the Patient-Assessed Acromegaly Symptom Questionnaire (PASQ). Results: The AcroQoL (P = 0.008) and AcroQoL physical (P = 0.002) improved significantly after PEG-V was added. The addition of PEG-V also significantly improved the PASQ (P = 0.038) and the single PASQ questions, perspiration (P = 0.024), soft tissue swelling (P = 0.036), and overall health status (P = 0.035). No significant change in Z-score of IGF-I (P = 0.34) was observed during addition of PEG-V. Transient liver enzyme elevations were observed in five subjects (25%). Conclusion: Improvement in quality of life was observed without significant change in IGF-I after the addition of 40 mg pegvisomant weekly to monthly SSA therapy in acromegalic patients who had normalized IGF-I on SSA monotherapy. These data question the current recommendations in how to assess disease activity in acromegaly. Moreover, the findings question the validity of the current approach of medical treatment in which pegvisomant is used only when SSA therapy has failed to normalize IGF-I.