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Background and Aim: Nasopharyngeal carcinoma (NPC) is one of the most common cancers in Southern China, Southeast Asia. Radiotherapy is the main treatment for NPC. Still, about 20% of patients with NPC have a recurrence. No effective serum biomarkers are available for recurrent nasopharyngeal carcinoma (rNPC) to date. This study aimed to explore whether amyloid beta (A4) precursor protein (APP) might serve as a valuable diagnostic and prognostic biomarker for patients with rNPC. Methods: In a previous study, a tandem mass tag–based proteomic test was performed, which screened 59 differentially expressed proteins (DEPs) between nonrecurrent nasopharyngeal carcinoma (nrNPC) and rNPC. In this study, a protein–protein interaction was conducted to screen the key proteins among the 59 DEPs. APP was validated and evaluated by enzyme-linked immunosorbent assay in 70 serum samples [recurrence (n = 35) and no-recurrence (n = 35)]. Also, the receiver operating characteristic (ROC) curve was plotted to evaluate the predictive value of APP. Results: The area under the ROC curve was 0.666 (95% CI: 0.514–0.818, P = 0.044). The best cutoff point of the relative expression levels for APP was 1.23 (concentration = 16.95 ng/mL), at which the sensitivity was 55.2% and the specificity was 90.9%. Conclusion: The findings indicated that APP might be a valuable diagnostic and prognostic biomarker for patients with rNPC. [ABSTRACT FROM AUTHOR]