OBJECTIVES:To perform a complete immunological characterization of compensatory anti-inflammatory response syndrome in patients with sepsis and to explore the relationship between these changes and clinical outcomes of 28-day mortality and secondary infections. DESIGN:Prospective single-center study conducted between April 2011 and December 2012. SETTING:ICUs from Hospital Universitario San Vicente Fundación at Medellin, Colombia. PATIENTS:One hundred forty-eight patients with severe sepsis. INTERVENTIONS:None. MEASUREMENTS AND MAIN RESULTS:At days 0, 1, 3, 5, 10, and 28, we determined the expression of HLA-DR in monocytes and the apoptosis and the proliferation index in T lymphocytes, as well as the levels of tumor necrosis factor-α, interleukin-6, interleukin-1β, interleukin-10, and transforming growth factor-β in both plasma and cell culture supernatants of peripheral blood mononuclear cells. The mean percentage of HLA-DR was 60.7 at enrollment and increased by 0.9% (95% CI, 0.7–1.2%) per day. The mean percentage of CD4 T cells and CD8 T cells AV+/7-AAD– at enrollment was 37.2% and 20.4%, respectively, but it diminished at a rate of –0.5% (95% CI, –0.7% to –0.3%) and –0.3% (95% CI, –0.4% to –0.2%) per day, respectively. Plasma levels of interleukin-6 and interleukin-10 were 290 and 166 pg/mL and decreased at a rate of –7.8 pg/mL (95% CI, –9.5 to –6.1 pg/mL) and –4 pg/mL (95% CI, –5.1 to –2.8 pg/mL) per day, respectively. After controlling for confounders, only sustained plasma levels of interleukin-6 increase the risk of death (hazard ratio 1.003; 95% CI, 1.001–1.006). CONCLUSIONS:We found no evidence to support a two-phase model of sepsis pathophysiology. However, immunological variables did behave in a mixed and time-dependent manner. Further studies should evaluate changes over time of interleukin-6 plasma levels as a prognostic biomarker for critically ill patients.