BACKGROUND: Understanding the factors influencing the occurrence and progression of nasopharyngeal carcinoma (NPC) is critical for reducing incidence rates and improving patient outcomes. The objective of this study is to preliminarily investigate the impact of Epstein-Barr virus (EBV) and cluster of differentiation (CD) lymphocytes on the prognosis of patients with advanced NPC. METHOD: A prospective cohort study design was employed, involving newly diagnosed patients with NPC confirmed by pathological diagnosis. Patients received standard radiotherapy and chemotherapy according to treatment guidelines, with regular follow-up assessments conducted. Prior to treatment initiation, patients underwent testing for EBV, blood biochemistry, and other parameters, while baseline data including patient age, pathology, and tumor node metastasis classification (TNM) staging were also collected. The primary outcome measure focused on disease progression. RESULTS: The analysis included a total of 99 cases, with a median age of 52 years, all of whom were stage III or IV patients. The median progression-free survival time for the patients was 45.53 months. After adjusting for confounding factors such as age, T stage, and metastasis, patients with low levels of B cells exhibited a 1.503-fold increased risk of progression compared to those with high levels of B cells (adjusted hazard ratio [HR] = 2.503
95% confidence interval [CI]: 1.062-5.899). Patients infected with EBV had a 1.739-fold increased risk of progression compared to uninfected patients (adjusted HR = 2.739
95% CI: 1.222-6.125). CONCLUSION: This study observed that patients with advanced nasopharyngeal carcinoma, infected with EBV and exhibiting diminished B cell levels, display heightened susceptibility to disease deterioration and progression.