Renal tubular function was studied in 14 patients chronically treated with lithium for affective disorders. Patients were separated into two groups according to the duration of lithium therapy: long-term (35 +/- 7.0 months) and short-term (4.8 +/- 0.8 months). At comparable urine lithium concentrations, patients on long-term therapy had a lower maximal urine osmolality (Umax) and free water reabsorption (TcH2O) than did patients on short-term therapy. The latter group achieved a Umax above 800 mOsm kg H2O. In contrast, both groups of patients failed to increase the urine-blood (U-B) Pco2 gradient normally during acute sodium bicarbonate loading. This low U-B Pco2 was observed at comparable urine bicarbonate concentrations between both groups of patients and controls, and thus was associated with a higher urine pH in patients. These findings indicate that the inability of these patients to achieve a normal U-B Pco2 in a maximally alkaline urine was the result of decreased distal hydrogen ion secretion rather than inability to raise urine bicarbonate concentrations as a result of a concentrating defect. Bicarbonate reabsorptive capacity was normal in our lithium-treated subjects. Both groups of patients achieved a normal U-B Pco2 gradient in response to sodium phosphate loading. They also were able to achieve a minimal urine pH and a maximal acid excretion similar to those of controls in response to a 3-day ammonium chloride loading test. Our data demonstrate that chronic lithium therapy is associated with a mild distal acidification defect disclosed only by the finding of a low U-B Pco2 gradient during sodium bicarbonate loading. This peculiar defect can be found in short-term lithium-treated patients in whom the concentrating capacity is relatively well preserved.