Rationale <p>Postoperative hypoalbuminemia is a common, persistent, and ominous abnormality following major surgery and has uncertain etiology. The purpose of this study was to investigate the incidence of protein-losing enteropathy as measured by alpha-1-antitrypsin clearance after major surgery.</p> Methods <p>We conducted a prospective cohort study of consecutive patients undergoing cardiac surgery at one hospital (n = 38, mean age = 65&#xa0;years, male = 79%). Alpha-1-antitrypsin was measured in both blood and stool samples using standard techniques for diagnosing protein-losing enteropathy. Sensitivity, specificity, and predictive indices were calculated taking into account the measured serum albumin concentration.</p> Findings <p>Postoperative hypoalbuminemia was a common finding and occurred in 82% of patients (95% confidence interval: 66 to 91). Paired analyses of blood and stool for alpha-1-antitrypsin clearance showed protein-losing enteropathy in 39% of patients (95% confidence interval: 26 to 55). Stool alpha-1-antitrypsin clearance for detecting postoperative hypoalbuminemia had a sensitivity of 48% (95% confidence interval: 30 to 67) and a specificity of 100% (95% confidence interval: 59 to 100). The positive predictive value was about 100% (95% confidence interval: 59 to 100).</p> Conclusions <p>We suggest protein-losing enteropathy may partially explain some cases of postoperative hypoalbuminemia after cardiac surgery.</p>