Plasma human prolactin (hPRL) was measured in 73 untreated acromegalic patients and was found to be elevated in 32% of the total population. Hyperprolactinemia was present in 40% of the females and in 27% of the male patients. In both groups, plasma hPRL correlated with plasma human growth hormone (hGH) levels with correlation coefficients of 0.38 (P less than 0.05) for females and 0.41 (P less than 0.005) for males. Forty-five patients were treated with conventional supervoltage pituitary irradiation and evaluated 2, 5, and 10 yr after treatment. The patients with hyperprolactinemia before irradiation showed a decrease in plasma hPRL at the most recent follow-up (mean +/- SEM, 125 +/- 34 vs. 67 +/- 15 ng/ml; P less than 0.01), although, in general, they did not achieve normal values. The patients who had normal plasma hPRL before irradiation (mean +/- SEM, 14 +/- 2 ng/ml) had increased levels after therapy (23 +/- ng/ml; P less than 0.005) but remained in the normal range during long term follow-up. In 10 patients followed for 1-10 yr without treatment, there was a tendency for plasma hPRL to rise progressively (mean increment, 122% above the initial value), with individual changes in hPRL strikingly parallel to the changes in plasma hGH. When serum hPRL was initially elevated, similar responses in both hormones were also seen in a small group of patients treated with surgical hypophysectomy. Galactorrhea was present in 5 of the 25 female patients; in 4 of the 5, plasma hPRL was within the normal range. Overall, these data suggest a closer relationship between hGH and hPRL in acromegaly than had been suspected, not only at the level of pituitary secretion but possibly also at the target cell.