Studies in mice suggest portal venous infusion of glucose at a low rate paradoxically causes hypoglycemia, which does not occur in dogs, rats and humans. A possible explanation is that fasting status in the mouse may have altered the response. We determined if the response to portal glucose delivery in the mouse was similar to that seen in other species and if it was dependent on the fasting status. Studies were performed on chronically catheterized conscious mice. Catheters were implanted (portal vein, jugular vein and carotid artery) 5 days prior to study. After a 5 or 16 h fast glucose was infused into either the portal (PO) or the jugular (JU) vein for 6 h at 25 µg/g/min. In 5h fasted mice PO and JU exhibited similar increases in arterial glucose from 155±11 to 173±19 mg/dl and 147±8 to 173±10 mg/dl, respectively. Tracer-determined endogenous glucose production decreased and insulin increased to the same extent in both PO and JU. A similar response was observed in 16h fasted mice, however the proportion of indirect glycogen synthesis was increased. In summary, portal glucose delivery in the mouse did not cause hypoglycemia even when the duration of the fast was extended. The explanation of the differing response from previous reports in the mouse is unclear.