The effect of glucocorticoid (GC) on the GC receptor in human peripheral lymphocytes was studies in vivo and in vitro. Excluding the effect of receptor occupancy, the GC receptor was measured by whole cell binding assay using [3H] dexamethasone as a ligand. The numbers of GC receptor in lymphocytes (whole cell, 8.42 +/- 1.88; nucleus, 3.56 +/- 1.38 fmoles/10(6) cells (M +/- SD) of patients treated with prednisolone (n = 26, mean: 33.7 mg/day) were significantly reduced when compared with those of normal subjects (n = 21; 10.48 +/- 2.40, 5.68 +/- 1.53) and those of patients without GC therapy (n = 9: 10.56 +/- 2.10, 5.26 +/- 1.07), respectively. The dissociation constants among these subjects were almost similar (5-7 nM). There were negative correlations between the receptor numbers (both whole cell and nucleus) of patients and daily dosage of prednisolone. The GC receptor numbers in both the whole cell and the nucleus were significantly decreased after 48 h in vitro preincubation with active GC. When new protein synthesis was blocked by cycloheximide (1 microgram/ml), GC did not reduce its own receptor number in vitro. Thus, the new protein synthesis may be required for this reduction in receptor number by GC. These results strongly suggest that GC down-regulates its own receptor in human peripheral lymphocytes.