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Ventilation in a prone position (PP) for 12 to 16 h per day improves survival in ARDS. However, the optimal duration of the intervention is unknown. We performed a prospective observational study to compare the efficacy and safety of a prolonged PP protocol with conventional prone ventilation in COVID-19-associated ARDS. Prone position was undertaken if P/F < 150 with FiO2 > 0.6 and PEEP > 10 cm H2O. Oxygenation parameters and respiratory mechanics were recorded before the first PP cycle, at the end of the PP cycle and 4 h after supination. We included 63 consecutive intubated patients with a mean age of 63.5 years. Of them, 37 (58.7%) underwent prolonged prone position (PPP group) and 26 (41.3%) standard prone position (SPP group). The median cycle duration for the SPP group was 20 h and for the PPP group 46 h (p < 0.001). No significant differences in oxygenation, respiratory mechanics, number of PP cycles and rate of complications were observed between groups. The 28-day survival was 78.4% in the PPP group versus 65.4% in the SPP group (p = 0.253). Extending the duration of PP was as safe and efficacious as conventional PP, but did not confer any survival benefit in a cohort of patients with severe ARDS due to COVID-19.