Adenosine stimulates hepatic glucose production in vitro. To investigate whether pentoxifylline, a xanthine derivative that blocks the adenosine receptor, inhibits basal glucose production, we measured hepatic glucose production in eight healthy postabsorptive subjects on two occasions: during continuous infusion of pentoxifylline and, in a control study, during saline infusion. Glucose production was measured by primed continuous infusion of [3-3H]glucose. Pentoxifylline infusion resulted in an approximately 22 (volume of distribution for glucose 40 ml/kg) to approximately 46% (volume of distribution for glucose 165 ml/kg) decrease in basal glucose production within approximately 1 h (P < 0.05), whereas in the control experiment glucose production declined by only approximately 4% in this time interval (P < 0.03 pentoxifylline vs. control). There were no differences in concentrations of insulin, C peptide, glucagon, or catecholamines between the two experiments. Because pentoxifylline inhibited glucose production in the absence of any changes in concentrations of glucoregulatory hormones, we conclude that pentoxyifylline inhibits hepatic glucose production through other mechanisms, e.g., by blocking the adenosine receptor.