The serum albumin concentration is used clinically as an indicator of nutritional status and as a prognostic indicator. Critically ill patients, who display many aspects of the acute phase response, frequently have low serum albumin levels upon hospitalization. Cytokines, such as tumor necrosis factor (TNF), mediate many aspects of the acute phase response. One purpose of this study was to determine if TNF administration to healthy well-nourished rabbits could produce hypoalbuminemia. After intravenous administration of saline or TNF, the TNF-treated rabbits experienced significant hypoalbuminemia which was most prominent at 24 h and was partially corrected by 48 h. A second purpose was to evaluate the effects of TNF treatment on transendothelial movement of albumin using an in vitro porcine pulmonary artery-endothelial cell system. Exposure to TNF for 24 h resulted in a dose dependent increase in transendothelial passage of albumin. These data suggest that the mechanisms of hypoalbuminemia frequently observed in critically ill patients can be explained in part by cytokine (TNF)-induced endothelial cell injury, which results in enhanced endothelial permeability to albumin. The hypoalbuminemia observed in many critically ill patients thus may be unrelated to nutritional status, but rather may be related to the patient's underlying disease state.