BACKGROUND: Prone positioning of patients with COVID-19 undergoing invasive mechanical ventilation (IMV) is widely used, but evidence of efficacy remains sparse. The COVID-19 Critical Care Consortium has generated one of the largest global datasets on the management and outcomes of critically ill COVID-19 patients. This prospective cohort study investigated the association between prone positioning and mortality and in particular focussed on timing of treatment. METHODS: We investigated the incidence, demographic profile, management and outcomes of proned patients undergoing IMV for COVID-19 in the study. We compared outcomes between patients prone positioned within 48 h of IMV to those (i) never proned, and (ii) proned only after 48 h. RESULTS: 3131 patients had data on prone positioning, 1482 (47%) were never proned, 1034 (33%) were proned within 48 h and 615 (20%) were proned only after 48 h of commencement of IMV. 28-day (hazard ratio 0.82, 95% confidence interval [CI] 0.68, 0.98, p = 0.03) and 90-day (hazard ratio 0.81, 95% CI 0.68, 0.96, p = 0.02) mortality risks were lower in those patients proned within 48 h of IMV compared to those never proned. However, there was no evidence for a statistically significant association between prone positioning after 48 h with 28-day (hazard ratio 0.93, 95% CI 0.75, 1.14, p = 0.47) or 90-day mortality (hazard ratio 0.95, 95% CI 0.78, 1.16, p = 0.59). CONCLUSIONS: Prone positioning is associated with improved outcomes in patients with COVID-19, but timing matters. We found no association between later proning and patient outcome.