Changes in cellular immunity and in lymphocyte populations have been studied in rats developing chronic renal insufficiency following 5/6 nephrectomy. Animals remain stable for a period of six months (BUN 40-60 mg/dl); then BUN slowly increases for 2-3 months, followed by rapid deterioration and death of the animals. Skin allotransplants showed no change in survival when transplanted fifteen weeks after nephrectomy; when transplanted 22 weeks and later after surgery, their survival was prolonged. The response of splenic cells in the mixed lymphocyte reaction (MLR) was unchanged for 15 weeks after surgery but became significantly reduced after 20 weeks. At the same time we observed an increased suppressor cell activity in splenic cell suspensions and an inhibitory effect of the uremic serum in the MLR. Resistance to tumor induction by syngeneic adenovirus 12-transformed cells was decreased in the late stages of uremia as measured by tumor development in these animals. Induction of cytolytic T cells in vitro was reduced at 24 weeks after operation; at 30 weeks virtually no cytolytic T cell activity was induced. There was also a decrease in natural killer cell activity in the late stages of uremia. These changes in immune response were correlated with the analysis of the lymphocyte sub-populations by staining with monoclonal antibodies and flow cytometry. During the development of uremia no significant changes were found in the lymph nodes. The thymus underwent a severe involution 20 weeks and later after nephrectomy. In the peripheral blood there was a significant decrease in the numbers of helper T cells. The helper T cell subset was also sharply reduced in the spleen of uremic rats at 20 weeks and later after operation.