Background: Major trauma affects the immune system, and immunosuppression may render the patients susceptible to septic complications. The purpose of this study was to investigate lipopolysaccharide (LPS)-induced releases of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in whole blood in patients undergoing total hip replacement. Methods: Seven patients (6 females) who underwent elective total hip replacement were included. Ex vivo LPS-induced releases of TNF-α and IL-6 were measured in a whole blood assay at days 1, 6, 9 and 12 postoperatively, using low- and high-dose LPS incubation. At the same time, white blood cell counts were analyzed. Results: The amount of TNF-α release was significantly reduced at days 6 and 12. Compared to monocyte counts, TNF-α release was significantly decreased also at day 9 in low- and high-dose LPS stimulation. IL-6 in plasma was significantly increased at day 1 and normalized thereafter. There were no differences in LPS-induced IL-6 levels compared to the levels before surgery. Conclusion: This in vivo/ex vivo study shows a reduced capacity of whole blood to release LPS-induced TNF-α at day 6 through to day 12 after major orthopedic surgery. Attenuated TNF-α release may contribute to an increased postoperative susceptibility to gram-negative sepsis.