Current treatment guidelines for sepsis claim an early goal-directed hemodynamic optimization including fluid resuscitation, use of vasopressors and inotropic agents. We investigated the correlation between the prominent treatment goal central venous saturation (ScvO2) and the frontal and the thenar regional oxygen saturation (rSO2) measured by near infrared spectroscopy. Secondary, we examined the value of ScvO2, lactate levels and rSO2 as surrogate markers of an impaired tissue oxygenation for outcome prediction in sepsis. This prospective, observational study was performed at the surgical intensive care unit of the University Hospital Giessen. A total of 50 patients with sepsis, severe sepsis or septic shock were included. ScvO2, rSO2 and lactate were measured at sepsis diagnosis (baseline), 24 and 48 h, thereafter. We investigated the predictive value of frontal and thenar rSO2 for a decreased SvcO2 under 70%. For survivor and non-survivors ScvO2, rSO2 and lactate were analysed. Patients with ScvO2 >70% showed a trend to higher levels of fontal rSO2 (62.81 ± 8.06 vs. 53.54 ± 15.48; p = 0.058). ROC-analysis revealed a minor prediction of a decreased ScvO2 by frontal rSO2 levels at baseline (AUC = 0.687; 95% CI 0.511-0.863; p = 0.047). Combined measurements of lactate and ScvO2 showed significantly elevated mortality for patients with ScvO2 ≥70% and lactate levels ≥2.5 mmol/l (log rank test p = 0.004). In the group with ScvO2 <70% and lactate levels <2.5 mmol/l no patients died during the observation period. Frontal rSO2 correlates with ScvO2 but both frontal and thenar rSO2 do not exactly discriminate between patients with high or low ScvO2 in sepsis. The combination of elevated lactate >2.5 mmol/l and ScvO2 >70 % is highly associated with poor outcome in ICU patients with sepsis, severe sepsis and septic shock.