Severe hypophosphatemia is known to be associated with respiratory failure, but there are few studies that specifically examine the relationship between serum phosphorus concentration and failure to wean patients from mechanical ventilation. This study investigated the association between hypophosphatemia and weaning failure in patients in two medical intensive care units (ICU). The study was conducted in a prospectively developed cohort of 66 patients being treated with ventilatory support and in whom 193 weaning trials were attempted. Ultimately, all 66 subjects were successfully weaned. A cross-sectional analysis was conducted on serum phosphorus levels and success or failure to wean the patients from ventilators. At the time of the successful weaning attempts (n = 66), the subjects' serum phosphorus concentrations (mean +/- SD) were 1.18 +/- 0.27 mmol/L, whereas at all failed weaning attempts (n = 127) serum phosphorus concentrations averaged 1.06 +/- 0.31 mmol/L (p = 0.008). Subjects with phosphorus concentrations below the reference interval (RI) in our laboratory (<0.80 mmol/L) had greater risk for weaning failure compared to subjects with phosphorus concentrations at or above the RI (relative risk = 1.18; 95% confidence interval = 1.06 to 1.32; p = 0.01). Serum calcium concentrations were not significantly different at the time of successful weaning compared to those at failed weaning attempts. This study indicates that there is an association between hypophosphatemia and failure-to-wean from mechanical ventilation in ICU patients on ventilatory support.