BACKGROUND Patients with undifferentiated nasopharyngeal carcinoma (NPC) have elevated serum levels of CYFRA 21‐1 (CYFRA), ferritin, and β‐2‐microglobulin (β2M) compared with healthy control individuals. The prognostic value of these markers has never been validated prospectively. METHODS Paired serum samples from 160 patients with newly diagnosed, nonmetastatic, undifferentiated NPC were collected before radiotherapy (RT) and at 4–6 weeks after the completion of RT. Pre‐RT and post‐RT levels of serum CYFRA, ferritin, and β2M were analyzed and correlated with overall survival (OS), progression‐free survival (PFS), time to locoregional recurrence, (TLR) and time to distant recurrence (TDR). The results of pre‐RT and post‐RT plasma Epstein–Barr virus (EBV) DNA levels available from a previous study were included in a Cox regression model together with age, tumor (T) classification, and lymph node (N) classification. RESULTS Sixty percent of patients had International Union Against Cancer Stage III–IV disease. At a median follow‐up of 116 weeks (range, 37–239 weeks), 38 patients had disease progression. On multivariate analysis, pre‐RT CYFRA and post‐RT EBV DNA levels were independent predictors of poor OS, post‐RT EBV DNA level and N classification predicted poor PFS and TDR; and only T classification predicted TLR. Patients who had pre‐RT CYFRA levels ≥ 1.5 U/mL were more likely to die (hazard ratio, 1.18; 95% confidence interval, 1.10–1.26) compared with patients who had pre‐RT CYFRA levels < 1.5 U/mL. There were no associations between age, post‐RT CYFRA levels and pre‐RT or post‐RT serum ferritin and β2M levels, and the survival and recurrence rates on multivariate analysis. CONCLUSIONS Serum CYFRA levels taken before RT predicted reduced survival in patients with nonmetastatic, undifferentiated NPC who underwent RT. Cancer 2004. © 2004 American Cancer Society.