1. The effects of acutely raising blood ketone body levels to those seen after 72 h of starvation were examined in 10 subjects after an overnight fast. Metabolic rate and respiratory exchange ratio were measured with indirect calorimetry before and during an insulin-glucose clamp. Arteriovenous differences were measured across forearm and subcutaneous abdominal adipose tissue. 2. In response to the clamp the respiratory exchange ratio rose from 0.82 to 0.83 during 3-hydroxybutyrate infusion and from 0.83 to 0.94 during control (saline) infusion (P < 0.001). 3. Forearm glucose uptake at the end of the clamp was 4.02 +/- 0.95 (3-hydroxybutyrate infusion) and 7.09 +/- 1.24 mmol min-1 100 ml-1 forearm (saline infusion). Whole body glucose uptake at the end of the clamp was 72.8 +/- 7.9 (3-hydroxybutyrate infusion) and 51.0 +/- 3.0 (saline infusion) mmol min-1 kg-1 body weight-1. 4. 3-Hydroxybutyrate infusion reduced the baseline abdominal venous-arterialized venous glycerol difference from 84 +/- 28 to 25 +/- 12 mmol/l and the non-esterified fatty acid difference from 0.60 +/- 0.17 to 0.02 +/- 0.09 mmol/l (P < 0.05 versus saline infusion). 5. Hyperketonaemia reduces adipose tissue lipolysis and decreases insulin-mediated forearm glucose uptake. Hyperketonaemia appears to prevent insulin-stimulated glucose oxidation, but does not reduce insulin-mediated glucose storage.