The relationship between the structural changes of the kidney and duration of lithium administration or lithium dosage was studied in rats. A diet containing LiCl was administered to mothers before birth and to the examined rats postnatally. Flattening and falling of the epithelium, exposure of the basal membrane and dilatation and cyst-building were observed in the proximal and distal tubules. Atrophy, necrosis, interstitial fibrosis and infiltration were observed in the glomeruli. These changes were seen at any age regardless of the dosage, and were not specific to lithium treatment. There were considerable individual variations in these changes. The number of cysts was higher in lithium treated rats, significantly so in the 20 mEq and 30 mEq dosage groups at 30 weeks. A significant elevation in the number of damaged glomeruli was found in the 20 mEq lithium groups at all ages. Long-term treatment with a large dosage of lithium could cause structural damages to the kidney. Renal function was studied in 92 patients whose average age was 44.8±13.3 years (16-73 years), and who had been treated for 30.8±23.0 months (6-108 months) with lithium carbonate 611±190 mg/day (200-1200mg/day). The serum lithium concentration was 0.41±0.14 mEq/l (0.2-1.0 mEq/l). Nine patients (10.5%) had low (below 1006) specific gravity of urine, and 3 patients (3.5%) had proteinuria, but their creatinine clearance, serum creatinine and urea nitrogen were within the normal range. The average creatinine clearance was 109.8±21.3 ml/min in men and 102.6±32.5 ml/min in women. Low creatinine clearance values were found in 9 patients (12.7%), but their other labobotory test results were normal. The levels of serum creatinine and urea nitrogen were not increased after lithium therapy. Lithium therapy at the level of 0.4 mEq/serum for 108 months should cause no serious renal dytfunction, though some patients may show slight changes such as low specific gravity of urine, proteinuria and low creatinine clearance.