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Background: Non-anatomical factors significantly affect treatment guidance and prognostic prediction in nasopharyngeal carcinoma (NPC) patients. Here, we developed a novel survival model by combining conventional TNM staging and serological indicators., Methods: We retrospectively enrolled 10,914 eligible patients with nonmetastatic NPC over 2009-2017 and randomly divided them into training (n = 7672) and validation (n = 3242) cohorts. The new staging system was constructed based on T category, N category, and pretreatment serological markers by using recursive partitioning analysis (RPA)., Results: In multivariate Cox analysis, pretreatment cell-free Epstein-Barr virus (cfEBV) DNA levels of >2000 copies/mL [HR OS (95 % CI) = 1.78 (1.57-2.02)], elevated lactate dehydrogenase (LDH) levels [HR OS (95 % CI) = 1.64 (1.41-1.92)], and C-reactive protein-to-albumin ratio (CAR) of >0.04 [HR OS (95 % CI) = 1.20 (1.07-1.34)] were associated with negative prognosis (all P < 0.05). Through RPA, we stratified patients into four risk groups: RPA I (n = 3209), RPA II (n = 2063), RPA III (n = 1263), and RPA IV (n = 1137), with 5-year overall survival (OS) rates of 93.2 %, 86.0 %, 80.6 %, and 71.9 % (all P < 0.001), respectively. Compared with the TNM staging system (eighth edition), RPA risk grouping demonstrated higher prognostic prediction efficacy in the training [area under the curve (AUC) = 0.661 vs. 0.631, P < 0.001] and validation (AUC = 0.687 vs. 0.654, P = 0.001) cohorts. Furthermore, our model could distinguish sensitive patients suitable for induction chemotherapy well., Conclusion: Our novel RPA staging model outperformed the current TNM staging system in prognostic prediction and clinical decision-making. We recommend incorporating cfEBV DNA, LDH, and CAR into the TNM staging system., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)