Previous studies have demonstrated a diabetogenic effect of Venezuelan equine encephalitis (VEE) virus in hamsters. A preliminary study was conducted in which five 2- to 3-year-old rhesus monkeys were infected with the virulent Trinidad donkey strain of VEE virus and their carbohydrate metabolism was studied over 10 months. All animals developed mild clinical illness (rhinorrhea, cough, fever), were viremic, and developed antibodies. As compared with the results of preinoculation intravenous glucose tolerance tests (IVGTT), the monkeys had abnormally high glucose values by 2 months postinoculation (PI), progressively diminished insulin responses between 8 days and 5 months PI, and significantly lower glucagon curves 2, 5, and 10 months PI. Pancreatic histology and insulin content were normal. A second, controlled study was conducted of glucose and insulin metabolism in somewhat older (3- to 8-year-old) rhesus monkey after they were infected with both the Trinidad donkey strain of VEE virus and the attenuated VEE vaccine (TC-83). Groups of six monkeys received the virulent virus and the TC-83 vaccine, and five animals were sham-inoculated with saline. Monkeys inoculated with virulent virus became viremic, and 50% became febrile without overt signs of illness, whereas those given TC-83 virus remained afebrile and did not become viremic, but five of six developed antibodies. Intravenous glucose tolerance tests were performed and serum immunoreactive insulin responses to glucose administration measured before infection and 2 and 5 months later. No significant and consistent alterations of glucose or insulin responses were detected in the infected or control groups. Although several animals had preinoculation anti-islet cell antibodies, none developed new antibodies during the study.