Background: Pulmonary arterial hypertension (PAH) is a serious complication of congenital heart defects (CHD), marked by high pulmonary pressure and increased risk of morbidity and mortality. Inflammation, endothelial dysfunction, and platelet activation are increasingly recognized in PAH pathogenesis. Soluble CD40 ligand (sCD40L), may serve as a novel biomarker in this setting. Aim: to evaluate serum levels of sCD40L in children with CHD and left-to-right shunts and to assess its diagnostic value for PAH. Methods: This case-control research has been performed at the Pediatric Cardiology Unit of Zagazig Children’s Hospital, Faculty of Medicine, Zagazig University. A total of 96 children were included and divided into two equal groups. Group 1 (n = 48) had CHD with PAH, and Group 2 (control) (n = 48) had CHD without PAH. All children underwent clinical evaluation, echocardiography, routine laboratory tests, and measurement of serum sCD40L using a sandwich ELISA. Results: Children with PAH had significantly lower hemoglobin and significantly higher C-reactive protein, bleeding time, and sCD40L levels compared with controls (all p < 0.05). Median 2 sCD40L was 3.35 ng/mL in the PAH group versus 1.20 ng/mL in the non-PAH group. Receiver operating characteristic analysis showed that a sCD40L level > 1.9 ng/mL can predict PAH in children with left-to-right shunt CHD with a sensitivity of 95.8% and a specificity of 100%. Conclusion: Serum sCD40L levels are significantly higher in children with PAH secondary to left-to-right shunt CHD, with excellent diagnostic performance, serving as a promising biomarker for PAH prediction in this high-risk pediatric population