Objective: The purpose of our study was to determine if central venous oxygen saturation and femoral venous oxygen saturation can be used interchangeably during surgery and in critically ill patients. Design: Prospective observational controlled study. Setting: Nonacademic university-affiliated teaching hospital in The Netherlands. Patients: One hundred cardiac outpatients, 30 high-risk surgical patients, and 30 critically ill patients. Interventions: None. Methods and Main Results: We concurrently determined femoral venous oxygen saturation and central venous oxygen saturation in a group of 100 stable cardiac patients, which served as control group. Furthermore, we determined simultaneously femoral venous oxygen saturation and central venous oxygen saturation in 30 surgical patients and in 30 critically ill patients and evaluated changes over time. Correlation and agreement of femoral venous oxygen saturation and central venous oxygen saturation were assessed, including the difference between femoral venous oxygen saturation and central venous oxygen saturation. Despite significant correlation between obtained values of fem oral venous oxygen saturation and central venous oxygen saturation (r s = 0.55; p < .001), the limits of agreement were wide in the control group (mean bias 2.7% ± 7.9%; 95% limits of agreement −12.9% to 18.2%). In both the surgical and critically ill patients, limits of agreement (mean bias of −1.9% ± 9.3%; 95% limits of agreement −20.0% to 16.3%, and mean bias of 4.6% ± 14.3%; 95% limits of agreement −23.5% to 32.6%, respectively) were wide. Results for changes of femoral venous oxygen saturation and central venous oxygen saturation were similar. During initial treatment of critically ill patients, the difference between femoral venous oxygen saturation and central venous oxygen saturation including its range of variation diminished. Conclusion: There is lack of agreement between femoral venous oxygen saturation and central venous oxygen saturation in both stable and unstable medical conditions. Thus, femoral venous oxygen saturation should not be used as surrogate for central venous oxygen saturation. (Crit Care Med 2012; 40:0–0)