The effect of alanine on ketone body levels, independent of hormonal changes, in normal man has been investigated. Five normal subjects were given somatostatin infusions (200 micrograms/hour) for 3 hr. After 1 hr alanine or isotonic saline was infused for 2 hr. With saline blood beta-hydroxybutyrate and acetoacetate levels rose steadily to a peak of 0.230 plus or minus 0.053 and 0.112 plus or minus 0.023 mmole/l respectively. With alanine beta-hydroxybutyrate and acetoacetate levels plateaued at 0.099 plus or minus 0.020 and 0.055 plus or minus 0.006 mmole/l respectively. Alanine levels reached nearly 1 mmole/l but a significant effect on ketone body levels was apparent at physiologic levels (less than 0.6 mmole/l). Plasma fatty acid and glycerol levels did not change significantly. Insulin C-peptide and glucagon levels were suppressed to a similar extent in both experiments. These results support the view that alanine suppresses ketogenesis in man by a direct hepatic effect independent of insulin and glucagon. It is suggested that this forms part of a negative feedback substrate cycle between alanine and ketone bodies.