To determine the hormonal status of somatostatin in man, plasma levels of ∼1600-dalton somatostatin-like immunoreactivity (SLI) were measured before and after a mixed meal. Plasma was subjected to gel filtration and the fractions coeluting with somatostatin were concentrated ninefold before radioimmunoassay. In this system the recovery of synthetic somatostatin added to plasma averaged 71 ± 4.6% (mean ± SE, N = 5). Synthetic somatostatin infused into normal volunteers gave a dose-related increase in the measured SLI value. Fasting SLI in 13 normal volunteers was 8.0 ± 0.7 pg/ml (mean ± SE) and rose to 18.6 ± 1.5 pg/ml and 20.3 ± 2.0 pg/ml at 60 and 120 min, respectively, after the meal (P < 0.001). In seven type I diabetics, the fasting level was 11.5 ± 1.6 pg/ml and the 60- and 120-min postprandial levels were 21.4 ± 2.5 and 22.3 ± 2.9 pg/ml, respectively. The meal-induced rise in ∼1600 M.W. SLI approximated that produced by infusing somatostatin at 2 μg/h, a rate that significantly suppressed glucagon levels. These results are therefore consistent with a hormonal role for somatostatin in man.