Background: Clinicians have begun using near-infrared spectroscopy (NIRS) to monitor tissue perfusion in hemorrhagic shock, as the technique allows continuous noninvasive monitoring of tissue hemoglobin oxygen saturation (StO2) and the tissue hemoglobin index (THI). We hypothesized that StO2 measurements in patients with severe sepsis would be associated with the severity of their illness and would correlate with invasive hemodynamic measurements. Methods: We measured mean arterial pressure (MAP), serum lactate concentration, blood hemoglobin concentration, StO2, and THI in nine healthy volunteers and ten patients with septic shock in a surgical intensive care unit (ICU). Enrolled patients had a pulmonary artery catheter, and had family able to give informed consent. The average Acute Physiology and Chronic Health Evaluation (APACHE) II score at enrollment for the patients was 19 ± 5 (standard deviation) points. Volunteers and patients were similar with respect to age and sex. To collect NIRS data, we used the InSpectra Tissue Spectrometer, Model 325 (Hutchinson Technology, Inc., Hutchinson, MN). For three consecutive days, we obtained invasive hemodynamic measurements three times daily, simultaneously with NIRS measurements, and metabolic cart measurements once daily. Results: Patients with severe sepsis had significantly lower thenar muscle StO2 values (p = 0.031) than healthy volunteers. Near-infrared spectroscopy-derived mixed venous oxygen saturation (NIRSvO2) and StO2 measured from the thenar eminence in patients with severe sepsis correlated with SvO2 from the pulmonary artery catheter (p < 0.05). In this group of patients, StO2 did not correlate significantly with lactate concentration, base deficit, or APACHE II score. Conclusions: Near-infrared spectroscopic measurements of StO2 correlated with invasive hemodynamic measurements in patients with severe sepsis but did not correlate with severity of illness. These findings suggest that NIRStO2 may be a clinically useful measurement in monitoring patients with severe sepsis. Further study of this device in early resuscitation of patients with sepsis is necessary.