Thalidomide, an agent which inhibits biosynthesis of tumor necrosis factor alpha (TNF-␣) and which is used to treat a variety of chronic inflammatory conditions, was investigated as therapy for experimental sepsis. Sepsis was induced by intraperitoneal injection of 10 7 CFU of Escherichia coli per kg of body weight to 80 Wistar rats divided into four groups. Group A consisted of 24 control animals that did not receive any pretreatment, group B consisted of 18 vehicle-treated control animals pretreated with seed oil, group C consisted of 30 rats administered thalidomide diluted in seed oil at a dose of 50 mg/kg 30 min before bacterial challenge, and group D consisted of eight animals that were not challenged with E. coli but that were used for white blood cell count determination. Sepsis was determined by measurement of vital signs before and 6 h after bacterial challenge. After 6 h the animals were killed and blood was sampled for culture; white blood cell count determination; and determination of endotoxin (lipopolysaccharide), TNF-␣, interleukin-1␤ (IL-1␤), and IL-6 levels. The levels of these cytokines were also estimated in the supernatants of human monocytes pretreated with thalidomide after exposure to the isolate. Sepsis developed in all vehicle-treated control animals and controls by 6 h after bacterial challenge but in only 10 animals (33.3%) pretreated with thalidomide (P < 0.0001). Six hours after bacterial challenge all animals had similar levels of endotoxemia, IL-1␤, and IL-6. The mean white blood cell count for groups A, B, and C were 5,631.1, 2,638.9, and 8,169.3 cells/l, respectively (P value between groups, <0.0001); the TNF-␣ levels were 77.3, 107.2, and 26.1 pg/ml, respectively (P values between groups, <0.0001). Pretreatment of human monocytes with thalidomide prevented the secretion of TNF-␣ and IL-1␤ but not that of IL-6. It is concluded that thalidomide exerts a considerable anti-inflammatory effect by preventing evolution to sepsis and by decreasing the level of production of TNF-␣ and therefore deserves to be further evaluated in research for the therapy of sepsis.Over the last decade the idea of inhibiting tumor necrosis factor alpha (TNF-␣) biosynthesis or TNF-␣ activity as an immunomodulatory therapy for sepsis caused by gram-negative organisms has been thoroughly explored with various animals and in clinical trials (4, 18). Results from recent human studies with the p55 tumor necrosis factor receptor protein (lenercept), however, were disappointing (1). Thalidomide is an old agent that in 1998 was approved for use by the Food and Drug Administration for the treatment of erythema nodosum leprosum. Since then, further knowledge on its immunomodulatory properties has been acquired. A major effect of this drug is reduction of the half-life of TNF-␣ mRNA in human monocytes (7). Thalidomide is used to treat a variety of dermatological conditions, such as cutaneous lupus erythematosus and Behçet's syndrome; various conditions associated with human immunodeficiency virus infection like apht...