Mortality in ARDS is correlated with the ventilatory ratio (VR, [minute ventilation × PaCO2]/[predicted body weight × 100 × 37.5]). This research aimed to determine if neuromuscular blockade (NMB) or preexisting disease severity influenced the association between virtual reality (VR) and mortality. Patients with moderate to severe ARDS were randomly assigned to receive NMB or placebo in this post hoc analysis of the PETAL-ROSE trial. Kaplan-Meier analysis compared patients’ survival rates based on their VR trajectories or VR cutoffs that were above and below the median. Logistic regression was used to examine the associations between VR trajectories over a single day versus those over 48 hours and 28 and 90-day mortality rates. Multivariable regression and interaction term analyses looked for potential confounders, including NMB allocation and illness severity markers. Patients whose VR was declining showed a worse 5-year survival rate than those whose VR was improving R (n = 602, P<0.05). Patients with VR more than 2 (median) on day 1 had a significantly lower 90-day survival compared to patients with VR less than or equal to 2 (HR 1.36, 95% CI 1.10–1.69). VR at day 1 was significantly associated with 28-day mortality (OR = 1.40, 95% CI 1.15–1.72). The 28-day mortality rate did not change based on the presence or absence of NMB or VR. Regarding the outcome of 28-day mortality, there was a significant interaction between APACHE-III and VR at baseline, with the association between VR and mortality being higher among individuals with lower APACHE-III. Increasing VR trajectory was significantly associated with mortality (Adjusted OR 1.81, 95% CI 1.28–2.84 for 28-day and OR 2.07 95% CI 1.41–3.10 for 90-day mortality) after controlling for NMB, baseline PaO2/FiO2 ratio, and other general markers of disease severity. APACHE-III or NMB did not moderate the association between VR progression and mortality. Increased 28-day mortality was seen in those with elevated baseline and day-1 VR. Patients with a lower APACHE-III score showed a higher association between VR at baseline and mortality. VR trajectory may be particularly well-suited for prognostication and predictive enrichment because APACHE-III did not act as an effect modifier for the association between the 2. Virtual reality (VR) did not differ between patients assigned to NMB and controls, suggesting that it can be used without needing NMB correction.