IGF-I levels normalize in the majority of patients with acromegaly treated with the GH receptor antagonist pegvisomant. To date, the efficacy of pegvisomant has been demonstrated with daily administration of doses ranging from 10 to 40 mg. However, given the known long half-life of the drug in circulation, we hypothesized that dosing less frequently than daily would still maintain the drug's efficacy. We studied ten patients with active acromegaly treated with pegvisomant. This therapy was begun at 10 mg daily, but then titrated up in dose or down to alternate day dosing to try to maintain serum IGF-I levels in the upper one half of the patients' age-adjusted normal range. We have found that in 5 of 10 patients serum IGF-I levels remained normal on less frequent than daily pegvisomant. Signs and symptoms of the disease and a disease related morbidity, insulin resistance, remained improved in these patients. We demonstrate for the first time the continued efficacy of alternate day administration of pegvisomant.