Background To date the description of mechanically ventilated patients with Coronavirus Disease 2019 (COVID-19) has focussed on admission characteristics with no consideration of the dynamic course of the disease. Here, we present a data-driven analysis of granular, daily data from a representative proportion of patients undergoing invasive mechanical ventilation (IMV) within the United Kingdom (UK) to evaluate the complete natural history of COVID-19. Methods We included adult patients undergoing IMV within 48 hours of ICU admission with complete clinical data until death or ICU discharge. We examined factors and trajectories that determined disease progression and responsiveness to ARDS interventions. Our data visualisation tool is available as a web-based widget (https://www.CovidUK.ICU). Findings Data for 623 adults with COVID-19 who were mechanically ventilated between 01 March 2020 and 31 August 2020 were analysed. Mortality, intensity of mechanical ventilation and severity of organ injury increased with severity of hypoxaemia. Median tidal volume per kg across all mandatory breaths was 5.6 [IQR 4.7-6.6] mL/kg based on reported body weight, but 7.0 [IQR 6.0-8.4] mL/kg based on calculated ideal body weight. Non-resolution of hypoxaemia over the first week of IMV was associated with higher ICU mortality (59.4% versus 16.3%; P<0.001). Of patients ventilated in prone position only 44% showed a positive oxygenation response. Non-responders to prone position show higher D-Dimers, troponin, cardiovascular SOFA, and higher ICU mortality (68.9% versus 29.7%; P<0.001). Multivariate analysis showed prone non-responsiveness being independently associated with higher lactate (hazard ratio 1.41, 95% CI 1.03–1.93), respiratory SOFA (hazard ratio 3.59, 95% CI 1.83–7.04); and cardiovascular SOFA score (hazard ratio 1.37, 95% CI 1.05–1.80). Interpretation A sizeable proportion of patients with progressive worsening of hypoxaemia were also refractory to evidence-based ARDS strategies and showed a higher mortality. Strategies for early recognition and management of COVID19 patients refractory to conventional management strategies will be critical to improving future outcomes. Competing Interest Statement The authors have declared no competing interest. Funding Statement This work was funded by the Imperial College London Covid-19 research fund and the Royal Brompton & Harefield Hospitals Charity. Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.