In order to define the mechanism of glucose intolerance in acutely uremic rats, various studies were carried out 24 hours after bilateral nephrectomy. Glucose removal following intravenous glucose was significantly (p is less than 0.001) decreased in uremic rats compared with sham-operated rats (k = 2.1 +/- 0.03 per cent vs. 5.1 +/- 0.2 per cent). This deterioration in glucose tolerance was associated with higher insulin levels in uremic rats from one to 40 minutes after glucose administration, suggesting that insulin resistance accounted for the decrease in glucose removal by uremic rats. To identify the site of the insulin resistance, we compared the ability of insulin to enhance net glucose uptake by isolated perfused liver and muscle (hindlimb) preparations obtained from uremic and sham-operated rats. Insulin suppressed glucose outflow from perfused livers of uremic rats at least as well as it did from livers of sham-operated rats, and suppression occurred at both maximal ( greater than 600 micromicron./ml.) and threshold (75 micromicron./ml.) perfusate insulin levels. In contrast, there was a significant decrease in the ability of insulin (mean perfusate level = 225 micromicron./ml.) to enhance glucose uptake of perfused hindlimbs of uremic as compared with sham-operated rats. These results suggest that the insulin resistance of acute uremia may be due primarily to decreased insulin-mediated uptake of glucose by skeletal muscle without any decrease in sensitivity of the liver to insulin.