The effects of prolonged starvation on reticuloendothelial system (RE) function and on the survival of animals following trauma were studied. Rats were fasted for 5% days (water ad lib) after which a two-cm midline incision was made and the cecum ligated (CL). Food and water were allowed 36 hr after CL and survival was measured over 5½ days. The mortality rate in these animals was 60% (15/25) compared to 0% (0/15) in CL rats fasted for 24 hr. Starvation alone for 7 days did not produce any deaths but after 11 days of starvation mortality was 100%. Another group of animals were fasted for 5½ days and were used to study RE function 10 hr following CL. There was no significant difference in the intravascular clearance rates of injected lipid emulsion in various groups of animals, indicating that total phagocytic function was not changed by prolonged starvation plus CL (SCL). However, emulsion retention in the spleen, expressed as per cent injected dose per gm tissue, decreased by 53% and the lung retention increased by 988% following SLC. Serum GOT levels were not affected by prolonged starvation alone; however, SCL resulted in its elevation (37 vs. 82 IU/ml). Hepatic ATP levels (μmoles/g) decreased from 2.47 to 1.95 following 5½ days starvation and following SCL, it decreased to 1.75. These results indicate that the increased metabolic demand following trauma (i.e., CL), coupled with prolonged starvation, alters RE function with splenic lipid emulsion uptake decreasing and pulmonary uptake increasing. The relationship of these findings to immune function remains to be determined. Although the precise cause of increased mortality is not known, altered metabolic and RE function may play a role. © 1981 by The Williams and Wilkins Co.