In an effort to manage the existing population of the endangered Florida manatee (Trichechus manatus latirostris), as many individuals as possible are rehabilitated from illness or injury and released back into the waters of the state of Florida. It is not uncommon, however, for manatees recaptured for health assessment following release from rehabilitation to have elevated concentrations of serum creatinine. Although such elevated levels would be indicative of kidney failure in most other mammals, problems associated with renal function have not been evident in these recaptured manatees. To determine the possible cause(s) of the serum creatinine increase, two captive Florida manatees were manipulated to simulate many of the environmental and physical changes that occur during and shortly after release. Routine chemical analyses of serum and urine, complete blood counts, serum cortisol concentrations, and lymphocyte proliferation responses were measured. Serum creatinine concentrations increased significantly in response to decreased food intake and changes in food type. The increases differed depending on the salinity of the water in which the animals were maintained. It was found that significant changes in urinary creatinine and serum creatine kinase occurred as well, but serum cortisol concentrations were elevated only during simulated transport. Lymphocyte proliferation assays indicated that immune function was potentially impaired by extreme levels of dietary restriction and by changes in salinity. These results suggest that serum creatinine elevations and subsequent effects on the immune system might be minimized by adapting manatees undergoing rehabilitation to the diet and salinity they would encounter following release. Zoo Biol 22:103–120, 2003. © 2003 Wiley-Liss, Inc.