Background: Identifying patients in the immunosuppressive phase of sepsis is essential for development of immunomodulatory therapies. Little data exists comparing the ability of the two most well-studied markers of sepsis-induced immunosuppression, human leukocyte antigen (HLA)-DR expression and lipopolysaccharide (LPS)-induced tumor necrosis factor alpha (TNF-α) production, to predict mortality and morbidity. The purpose of this study was to compare HLA-DR expression and LPS-induced TNF-α production as predictors of 28-day mortality and acquisition of secondary infections in adult septic patients. Methods: A single-center, prospective observational study of 83 adult septic patients admitted to a medical or surgical intensive care unit. Blood samples were collected at three time points during the septic course (days 1-2, days 3-4, and days 6-8 after sepsis diagnosis) and assayed for HLA-DR expression and LPS-induced TNF-α production. A repeated measures mixed model analysis was used to compare values of these immunological markers among survivors and non-survivors and among those who did and did not develop a secondary infection. Results: Twenty-five patients (30.1 %) died within 28 days of sepsis diagnosis. HLA-DR expression was significantly lower in non-survivors as compared to survivors on days 3-4 (p = 0.04) and days 6-8 (p = 0.002). The change in HLA-DR from days 1-2 to days 6-8 was also lower in non-survivors (p = 0.04). Median HLA-DR expression decreased from days 1-2 to days 3-4 in patients who developed secondary infections while it increased in those without secondary infections (p = 0.054). TNF-α production did not differ between survivors and non-survivors or between patients who did and did not develop a secondary infection. Conclusions: Monocyte HLA-DR expression may be a more accurate predictor of mortality and acquisition of secondary infections than LPS-stimulated TNF-α production in adult medical and surgical critically ill patients.