The in vivo effect of glucose per se on blood ketone bodies, glycerol, and nonesterified fatty acids (NEFA) has been investigated in five normal (60 hours fasted) men receiving a somatostatin (SRIF) infusion (500 micrograms/h-1). When glycemia was raised over 10 mmol/L for 180 minutes by exogenous IV glucose infusion, neither insulin nor C peptide increase. NEFA and glycerol returned to fasting value in 40 minutes and remained stable. Ketone bodies decreased continuously and were significantly below the fasting values at the end of the study (1.3 +/- 0.3 mmol/L v 2.2 +/- 0.4 mmol/L, P less than 0.05). In order to ascertain whether glucose has been acting only on lipolysis or also on the liver ketogenic capacity, its effect was studied in vitro on isolated liver cells from 24-hour starved rats incubated with various amounts of palmitate. Glucose (30 mmol/L) did not affect the maximal ketogenic capacity (80 mumol/g (w/w)/h) measured with 1.6 mmol/L palmitate but increased the apparent palmitate K 0.5 for ketogenesis from 0.16 to 0.3 mmol/L. At physiologic free fatty acids concentration (0.22 mmol/L), glucose decreased ketogenesis by 90%. The effect was time-dependent, maximum after 30 minutes of incubation. Half-maximum inhibition by glucose was obtained at 6 mmol/L, a concentration at which lactate production was unaffected. These results suggest that glucose per se inhibits ketogenesis in vivo by acting probably both on lipolysis and on liver ketogenic capacity.