BACKGROUND: Ventilatory ratio (VR) has been proposed as an alternative approach to estimate physiological dead space. However, the absolute value of VR, at constant dead space, might be affected by venous admixture and CO(2) volume expired per minute (VCO(2)). METHODS: This was a retrospective, observational study of mechanically ventilated patients with acute respiratory distress syndrome (ARDS) in the UK and Italy. Venous admixture was either directly measured or estimated using the surrogate measure Pa(O)(2)/FiO(2) ratio. VCO(2) was estimated through the resting energy expenditure derived from the Harris-Benedict formula. RESULTS: A total of 641 mechanically ventilated patients with mild (n=65), moderate (n=363), or severe (n=213) ARDS were studied. Venous admixture was measured (n=153 patients) or estimated using the Pa(O)(2)/FiO(2) ratio (n=448). The VR increased exponentially as a function of the dead space, and the absolute values of this relationship were a function of VCO(2). At a physiological dead space of 0.6, VR was 1.1, 1.4, and 1.7 in patients with VCO(2) equal to 200, 250, and 300, respectively. VR was independently associated with mortality (odds ratio [OR]=2.5; 95% confidence interval [CI], 1.8-3.5), but was not associated when adjusted for V(D)/V(Tphys), VCO(2), Pa(O)(2)/FiO(2) (OR(adj)=1.2; 95% CI, 0.7-2.1). These three variables remained independent predictors of ICU mortality (V(D)/V(Tphys) [OR(adj)=17.9; 95% CI, 1.8-185; P<0.05]; VCO(2) [OR(adj)=0.99; 95% CI, 0.99-1.00; P<0.001]; and Pa(O)(2)/FiO(2) (OR(adj)=0.99; 95% CI, 0.99-1.00; P<0.001]). CONCLUSIONS: VR is a useful aggregate variable associated with outcome, but variables not associated with ventilation (VCO(2) and venous admixture) strongly contribute to the high values of VR seen in patients with severe illness.