Background <p>The clinical significance of early postnatal ETCOc in the prediction of phototherapy (PT) for neonatal hyperbilirubinemia has not been fully characterized. We aimed to investigate the relationship between early postnatal ETCOc and the risk of PT within 7 days of life (7 DOLs) and diagnostic performance.</p> Methods <p>This is a secondary analysis of the infants randomized to the control group of the HEME trial. Cases were infants who had PT within 7 DOLs and controls were infants who did not require PT. Multivariate logistic regressions were used for the analyses of phototherapy and early postnatal ETCOc, adjusting for transcutaneous bilirubin level, gestational age, birth weight, sex and maternal blood types. We also evaluated the predictive performance of ETCOc by comparing multiple diagnostic parameters.</p> Results <p>In 1,219 infants included, early postnatal ETCOc was associated with 2.98-(95% confidence interval [CI] = 2.22, 4.00, &lt; 0.01), 2.53-(95%CI = 1.65, 3.90, &lt; 0.01) and 2.42(95%CI = 1.05, 5.61, &lt; 0.01)-fold increased odds of PT, respectively. Each one-unit increment of ETCOc was associated with earlier initiation, longer duration and more courses of PT. The ETCOc had a sensitivity of 65.4–87.5%, specificity of 71.7–75.8%, positive predictive values of 41.0–51.6%, and negative predictive values of 87.3–95.3%, with area under curves of 0.732–0.880 for the outcome of PT.</p> Conclusions <p>A higher early postnatal ETCOc is linked with an increased risk of PT and PT characteristics within 7 DOLs. Early postnatal ETCOc can be a valuable indicator for predicting PT in early postnatal period.</p> Trial registration <p>: Registration identifier ChiCTR2100051476 of the Chinese Clinical Trial Registry (<a href="https://www.chictr.org.cn/">https://www.chictr.org.cn/</a>).</p>