Light and electron microscopy were used to study the effects of a lithium-supplemented diet on renal structure in the rat. At the end of a 7-week experimental period serum lithium levels were 1.14 ± 0.20m M. Lesions consisting of groups of dilated tubules were found in the immediate vicinity of the interlobular arteries in all experimental animals. These tubules were identified as the connecting tubule or the initial portion of the collecting tubule. The epithelium of these tubules was generally flattened but was punctuated by markedly swollen epithelial cells. PAS-positive deposits found in both types of cells were identified as glycogen. Electron microscopy revealed considerable lithium-induced damage in the swollen cells including increased numbers of mitochondria, many of which were swollen or otherwise damaged, dilated cisternae of endoplasmic reticulum and vacuolization of the apical cytoplasm. The flattened cells of these tubules were similar to the dark or intercalated cells of normal collecting tubules. Some detachment of epithelial cells from their basement membrane was evident in these tubules. Damage was less severe in distal convoluted tubules. Lithium-induced changes were not observed in glomeruli, proximal tubules or ascending thick limbs of Henle. In medullary collecting tubules damage was less severe than in cortical collecting tubules, but detachment of epithelial cells was a common finding. The interstitial tissue of the papilla exhibited histochemical and ultrastructural changes consistant with lithium blockade of the action of antidiuretic hormone. The ultrastructural damage to cortical tubules is similar to that found in patients receiving therapeutic lithium for long periods of time. The anatomic sites of lithium-induced pathology correspond to the location of lithium-induced pathophysiology.