Introduction: Prophylactic use of noninvasive ventilation (NIV) is recommended following extubation in patients at high risk of extubation failure. In a prospective cohort study, we examined the impact of prophylactic NIV in this subset of patients, potentially exploring the risk factors for extubation failure in them and the impact of extubation failure on organ function. We also explored the effect of fluid balance on extubation failure or success in this high-risk patient subgroup. Materials and methods: Consecutive adult patients (≥18 years) admitted in the mixed intensive care unit (ICU) of a tertiary care center, between January 1, 2018, and December 31, 2019, who passed a spontaneous breathing trial (SBT) following at least 12 hours of invasive mechanical ventilation and put on prophylactic NIV for being at a high risk of extubation failure, were prospectively followed throughout their hospital stay. Extubation failure was defined as developing respiratory failure within 72 hours postextubation requiring reintubation or still requiring NIV support at 72 hours postextubation. Results: A total of 85 patients were included in the study. 11.8% of patients had extubation failure at 72 hours with an overall reintubation rate of 10.5%. Higher age (p < 0.05), longer duration of invasive ventilation (p < 0.05), and higher sequential organ failure assessment (SOFA) score at extubation (p < 0.05) were identified as risk factors for extubation failure in univariate analysis. However, in the multivariate analysis, only a higher SOFA score remained statistically significant in forward logistic regression analysis (p < 0.05). We found a clear trend toward worsening organ function score in the extubation failure group in the first 72 hours postextubation, suggesting extubation failure as a risk factor for organ dysfunction. Cumulative fluid balance was higher both at extubation and in subsequent 3 days postextubation in the failure group, but the differences were not statistically significant. Conclusion: Higher age, longer duration of invasive ventilation, and higher baseline SOFA score at extubation remain risk factors for extubation failure even in this high-risk subset of patients on prophylactic NIV. Extubation failure is associated with the worsening of organ function. A trend toward higher cumulative fluid balance both at extubation and postextubation, suggests aggressive de-resuscitation as a potentially helpful strategy in preventing extubation failure.