Sepsis and starvation are catabolic conditions often occurring simultaneously. We recently found that uptake of the nonmetabolized amino acid analog, alpha-aminoisobutyrate (AIB), was reduced in skeletal muscle during sepsis, and data were presented suggesting that this reduction was caused by a factor present in septic plasma. The purpose of the present study was to determine the effect of starvation on amino acid uptake and to investigate possible interactions between sepsis and starvation regarding effects on muscle amino acid uptake. Soleus muscles were removed intact from rats fasted for 0, 24, 48, or 72 hr. Muscles were incubated for 2 hr in Krebs-Henseleit bicarbonate buffer (pH 7.4) and glucose (5 mM) with or without 0.25 ml of septic plasma (total volume 3 ml). Muscle AIB uptake progressively decreased by approximately 50% during the first 48 hr of starvation, with no further decrease at 72 hr. Addition of septic plasma in vitro reduced AIB uptake in muscles from fed rats and from rats which had been fasted for 24 hr, but did not further reduce uptake after longer periods of starvation. The results suggest that starvation reduces amino acid uptake in skeletal muscle and that the nutritional status of muscle is an important component of the response to the factor(s) in septic plasma capable of inhibiting amino acid uptake.