Objectives: Weaning protocols establish readiness-to-wean criteria to determine the opportune moment to conduct a spontaneous breathing trial. Weaning protocols have not been widely adopted or evaluated in ICUs in low- and middle-income countries. We sought to compare clinical outcomes between participants whose weaning trials were retrospectively determined to have been premature, opportune, or delayed based on when they met readiness-to-wean criteria. Design: Prospective, multicenter observational study. Setting: Five medical ICUs in four public hospitals in Lima, Perú. Subjects: Adults with acute respiratory failure and at least 24 hours of invasive mechanical ventilation (n = 1,657). Interventions: None. Measurements and Main Results: We established six readiness-to-wean criteria and retrospectively categorized our sample into three weaning groups: 1) premature: if the weaning trial took place before fulfilling all criteria, 2) opportune: if the weaning trial took place within 24 hours after fulfilling the criteria, and 3) delayed: if the weaning trial took place over 24 hours after fulfilling criteria. We compared 90-day mortality, ventilator-free days, ICU-free days, and hospital-free days between premature, opportune, and delayed weaning groups. In our sample, 761 participants (60.8%) were classified as having a premature weaning trial, 196 underwent opportune weaning (15.7%), and 295 experienced delayed weaning (23.6%). There was no significant difference in 90-day mortality between the groups. Both the premature and delayed weaning groups had poorer clinical outcomes with fewer ventilator-free days (–2.18, p = 0.008) and (–3.49, p < 0.001), ICU-free days (–2.25, p = 0.001) and (–3.72, p < 0.001), and hospital-free days (–2.76, p = 0.044) and (–4.53, p = 0.004), respectively, compared with the opportune weaning group. Conclusions: Better clinical outcomes occur with opportune weaning compared with premature and delayed weaning. If readiness-to-wean criteria can be applied in resource-limited settings, it may improve ICU outcomes associated with opportune weaning.