To assess the frequency with which acromegaly is caused by ectopic secretion of GRF, we collected plasma samples from 177 unselected acromegalic patients. The samples together with those of three acromegalic patients with previously diagnosed tumors secreting GRF and of normal subjects were assayed in 3 independent GRF RIAs. Plasma immunoreactive GRF (IR-GRF) levels in normal subjects were either undetectable or detectable at levels up to 62.5 pg/ml. In none of the 177 specimens from acromegalic patients were IR-GRF values detectable in all assays, and in the most sensitive assay, the levels were similar to those in normal subjects, with the highest level measuring 82 pg/ml. In contrast, plasma IR-GRF found in the 3 patients with tumors that secreted GRF ranged from 2.0-24.4 ng/ml. These data suggest that extrahypothalamic GRF secretion is a rare cause of acromegaly. However, it is important that this rare cause of acromegaly be diagnosed before the patient has unnecessary surgery and/or irradiation directed at the pituitary. We recommend that plasma IR-GRF be measured in each new acromegalic patient.