To investigate the effect of chronic hyperglucagonemia on hepatic metabolism, we have studied net splanchnic glucose and ketone body production rates in a patient with glucagonoma before and after complete tumor resection. Preoperatively, immunoreactive glucagon (IRG) concentration was high (1,800 pg. per milliliter) and the molar insulin/glucagon (I/G) ratio was low (0.4). Arterial free fatty acid (FFA) concentration (0.74 mM) and net splanchnic FFA uptake (0.27 mmole per minute) were normal. However, 48 per cent of the net splanchnic FFA uptake was utilized for net splanchnic ketone body production, which was four times (0.52 mmole per minute) greater than normal. Postoperatively IRG (40 to 150 pg. per milliliter) and the molar I/G ratio (> 1.0) were both normal. Arterial FFA concentration and net splanchnic FFA uptake were unchanged (0.67 mM and 0.27 mmole per minute, respectively). However, only 19 per cent of the net splanchnic FFA uptake was utilized for net splanchnic ketone body production, which had declined to 0.19 mmole per minute. These data suggest that chronic hyperglucagonemia in this patient had a stimulating effect on ketogenesis. Preoperatively, the net splanchnic glucose production rate was 0.56 mmole per minute and could be accounted for entirely by gluconeogenesis from lactate (83 per cent), pyruvate (9 per cent), glycerol (14 per cent), and alanine, glutamine, and glutamate (8 per cent). The abnormally large contribution of lactate to gluconeogenesis was an effect of inappropriately elevated lactate concentration (0.88 mM) and increased blood flow (2,400 ml. per minute). Postoperatively the net splanchnic glucose production rate was 0.67 mmole per minute, of which 51 per cent could be accounted for by gluconeogenesis. The data provide no evidence for an effect of chronic hyperglucagonemia on splanchnic glucose production. However, they do not exclude a small stimulating glucagon effect on gluconeogenesis from amino acids.