Background: Previous studies had shown that increasing energy intake in anorexic TNF- treated rats increased morbidity, due to stabilization of TNF activity by soluble and membrane TNFR. Although, protein supplementation reduces septic morbidity, its effect on TNF and TNFR are unknown. Objective: To determine the effect of low protein intake and supplementation on TNF and TNFR. Design: Thirty male wistar rats weighing 250 g, were fed a liquid defined formula diet for 10 days and randomly allocated to:(i)Controls(C; n=6): receiving normal energy and protein energy density of 0.047 MJ per 60 ml and NS(ii)Low protein(LP; n=6):receiving normal energy but a reduced protein-energy density of 0.012 MJ per 60 ml and LPS.(iii)Refeeding (RF; n=6):the rats were initially depleted on low protein diet(10 d) and then repleted on normal protein(10 d)while receiving LPS.(iv)Pair-fed (P-F; n=12):Individual P-F rats were paired with individual LP or RF rats receiving NS. Protein and mRNA expression of TNF, TNFR-1 and TNFR-11 in liver, spleen and gastrocnemius were measured by Western and RT-PCR, respectively. Results: In the liver the changes in TNF, TNFR-1 and TNFR-11 were translational, whereas, in spleen the effects were due to a combination of transcription/translation. In the gastrocnemius the effects were transcriptional/translational for TNFRs. In contrast, TNF mRNA was significantly increased but, TNF protein expression was reduced in LP rats as compared with controls and refed groups. Conclusion: Protein deficiency in endotoxic rats increases the expression of TNFR-1 and TNFR-11 in all organs studied and TNF in selected ones. This increase is suppressed by refeeding protein. Differential pattern between translation and transcription of TNF and its receptors is present. Our data suggests that protein restriction may be deleterious in sepsis.