In order to evaluate effects of metabolic acidosis on glucose metabolism in uremia, we studied, by an intravenous glucose tolerance test (IVGTT), 46 patients with severe chronic renal failure divided into three groups according to their blood bicarbonate (BB) values: group A formed by 15 patients without or with light metabolic acidosis (BB ≥ 20 mEq/l); group B formed by 18 patients with moderate metabolic acidosis (16 ≤ BB < 20 mEq/l); group C formed by 13 patients with severe metabolic acidosis (BB < 16 mEq/l). In 8 patients of group B (subgroup Bl) and in 8 of group C (subgroup Cl), IVGTT was also repeated after adjustment of acid-base balance by intravenous or oral bicarbonate administration. Twenty-nine healthy volunteers formed the normal controls. For each test, glucose constant decay (K), immunoreactive insulin (IRI) area and C-peptide (C-p) area response, insulinogenic index (IGI) and insulin resistance index (RI) were calculated. Compared to controls, all uremic groups showed significantly lower values of K and IGI and significantly higher values of C-p area and RI. In group C, RI was significantly higher than in groups A and B. No differences were found in the other glucose metabolism parameters among the uremic groups. After bicarbonate administration, subgroup Cl showed a significant decrease in RI and a rise in K values, while subgroup Bl showed no changes in glucose metabolism parameters. From these data, we infer that abnormalities of acid-base balance do not affect insulin response but severe metabolic acidosis may play an additional role in the insulin resistance of uremic patients.