Glucose intolerance occurs in patients with sepsis, and resistance to insulin has been thought to be part of this process. To study this phenomenon, peritonitis was produced in rats by cecal ligation and puncture. One group was killed ten hours later (early sepsis). A second group of rats was killed 16 to 24 hours after ligation, just prior to their expected death (late sepsis). Insulin stimulated glucose uptake to the same extent in muscles from rats in early sepsis, late sepsis, and from control rats. Even at an insulin concentration that produced submaximal stimulation of glucose uptake, no difference in glucose uptake between the three groups of muscles was observed. Thus, there was no resistance to the stimulatory action of insulin on glucose uptake by skeletal muscle during early and late sepsis. However, basal glucose uptake by isolated soleus muscle from animals in late sepsis was significantly increased compared with controls when these muscles were incubated in an aerobic environment. Under anaerobic conditions, glucose uptake in these two groups of muscles increased to the same level. This indicates that there is some stimulus that increases glucose uptake in late peritonitis and may explain the hypoglycemia of late experimental or untreated sepsis. This stimulus could be hypoxia or some other factor resulting from decreased blood flow and increased anaerobic metabolism.