Background: Late onset sepsis (LOS) is an important cause of serious illness and deaths among neonates.  Diagnosis of neonatal sepsis remains a challenge owing to nonspecific early clinical signs and the non-availability of a reliable biomarker. Serum amyloid A (SAA), the precursor protein in inflammation-associated reactive amyloidosis, whose level in the blood increases up to 1000 fold in response to inflammation and it is also an acute phase reactant like PCT and CRP. Objectives: assessing the accuracy and rapidity of SAA in detection of LOS in neonates. Method: This is a case-control study which was carried out on neonates admitted in (NICU) of Benha University Hospital and Benha Teaching Hospital during the period (from June 2018 to November 2019). Group 1 (patients group): 45 neonates with neonatal sepsis, group 2 (control group): 40 healthy neonates age and sex matched. SAA was measured. Results: mean value of SAA in septic group was 38.8 µg/ml compared to 1.26 µg/ml in control group , with statistically significant increase in patients than controls (p<0.001). ROC curve was done to show the performance of SAA in the prediction of LOS. It was found that at a cut-off value of SAA >2.8 µg/ml, SAA had a sensitivity 86.7%, specificity 85%, PPV 86.7%, and NPV 85% for early diagnosis of LOS. At a cut-off value of SAA>45.2 µg/ml, SAA had a sensitivity 83.3%, specificity 69.7%, PPV 50%, and NPV 92% for the prediction of mortality among LOS patients. Conclusion: The high sensitivity, specificity, positive predictive value and negative predictive value of SAA protein could help the clinicians for early diagnosis of LOS.