The question as to whether there is lactotroph resistance to dopamine (DA) in pathological hyperprolactinemia (PHP) is unresolved. Previous studies utilizing low-dose DA infusions to study lactotroph function have not considered the diurnal changes in prolactin (PRL) secretion that occur in normals but which are lost in PHP. As PRL levels show a fall in the hours after waking, studies performed during this time of day will falsely show a greater fall of PRL in normals than in PHP patients. The aim was to readdress the issue of lactotroph sensitivity using a study designed to minimize the problem arising from diurnal PRL changes. Eight normal subjects, 17 patients with PHP, and 6 hyperprolactinemic patients with nonfuncitoning pituitary tumors (NFTs) were studied with three graded doses of DA – (0.01, 0.05, and 0.5 µg/kg · min) – by relating the changes induced by each dose to the maximal spontaneous fall in PRL that occurred during a 3-hour control saline study. The mean ±SE maximal fall in PRL during control saline infusion to 46.0 ±4.1% of basal in normal subjects was significantly greater (p < 0.001) than the fall in patients with PHP (88.0 ± 1.0%) or NFTs (87.5 ± 2.6%). The apparent fall in PRL was significantly greater in normals during the two lower infusion doses, but not at the highest dose. When the changes in PRL during each infusion dose were corrected for the nadir achieved during the control saline study, no significant differences were observed at the two lower doses, whilst the 0.5-µg/(kg·min) dose induced a significantly greater (p < 0.05) fall in patients with PHP (26.1 ± 2.0%) and NFTs (22.4 ± 2.0%) than in normal subjects (42.6 ± 6.9%). Plasma DA was significantly higher in the PHP group than in normal subjects during 0.05-(0.93 ± 0.09 vs. 0.58 ±0.05 ng/ml) and 0.5-µg/(kg·min) infusions (5.18 ± 0.54 vs. 3.0 ± 0.22 ng/ml) but not significantly different from the NFT group (0.80 ±0.12 and 4.5 ±0.48 ng/ml, respectively). PRL suppression was negatively correlated with log plasma DA concentration. There was no significant difference in the slopes of the regression lines between the three groups studied. Patients with PHP are as responsive to doses of DA that produced DA levels in the physiological range as normal subjects or patients with NFTs. The diurnal fall of PRL secretion falsely exaggerates the effect of DA in normal subjects. We conclude that the data favor a model of DA deficiency rather than of lactotroph resistance in t