Abstract Background Hypothermia is associated with adverse outcome in patients with sepsis. The objective of this study was to characterize the host immune response in patients with hypothermic sepsis in order to determine if an excessive anti-inflammatory response could explain immunosuppression and adverse outcome. Markers of endothelial activation and integrity were also measured to explore potential alternative mechanisms of hypothermia. Finally we studied risk factors for hypothermia in an attempt to find new clues to the etiology of hypothermia in sepsis. Methods Consecutive patients diagnosed with sepsis within 24 hours after admission to ICUs in two tertiary hospitals in the Netherlands were included in the study ( n = 525). Hypothermia was defined as body temperature below 36 °C in the first 24 h of ICU admission. Results Hypothermia was identified in 186 patients and was independently associated with mortality. Levels of proinflammatory and anti-inflammatory cytokines were not different between groups. Hypothermia was also not associated with an altered response to ex vivo stimulation with lipopolysaccharide in a subset of 15 patients. Risk factors for hypothermia included low body mass index, hypertension and chronic cardiovascular insufficiency. Levels of the endothelial activation marker fractalkine were increased during the first 4 days of ICU stay. Conclusions Hypothermia during sepsis is independently associated with mortality, which cannot be attributed to alterations in the host immune responses that were measured in this study. Given that risk factors for hypothermic sepsis are mainly cardiovascular and that the endothelial activation marker fractalkine increased in hypothermia, these findings may suggest that vascular dysfunction plays a role in hypothermic sepsis.