Abstract: Background: Sepsis is a leading cause of mortality in neonatal foals. Early diagnosis is key to improved outcomes, but the diagnosis remains difficult. Soluble CD14 (sCD14) is a promising biomarker for inflammatory diseases in humans, including sepsis. Hypothesis/Objectives: Sick foals have higher serum sCD14 concentrations than healthy foals, and septic foals have higher sCD14 concentrations as compared to sick, nonseptic and healthy foals. Animals: 63 sick (29 septic, 34 nonseptic) and 26 healthy neonatal Thoroughbred foals. Methods: Prospective observational study. Blood samples were collected from hospitalized foals at admission, d3 and prior to discharge or death, and healthy foals on days 1,3 and 5 of life. Sick foals were categorized as septic or sick, non-septic based on sepsis score and blood culture results. Serum sCD14 was measured using a previously validated fluorescent bead-based assay. Results: On day 3, the sick foals combined (962.0, 432.0-2002.0 ng/mL) had higher sCD14 as compared to healthy foals (769.5, 482-1154 ng/mL, P=0.0009). At the last collection time, sCD14 was significantly greater in non-survivors (1504 ng/mL, 1443-1589) compared to surviving foals (760.0 ng/mL, 357.0-1950; P=0.02) and healthy foals (756.0 ng/mL, 481.0-1381.0) (P=0.03). There were no differences between septic and sick, nonseptic foals at any time point. Conclusions and clinical importance: Serum sCD14 concentrations were increased in critically ill foals and non-survivors. sCD14 could be an adjunctive biomarker of neonatal health status, along with other clinical and clinicopathologic data. However, sCD14 is not necessarily specific to sepsis and there is considerable overlap between sick and healthy foals.