PURPOSE: This study was conducted to evaluate the prognostic value of treatment-related lymphopenia in patients with nasopharyngeal carcinoma (NPC). MATERIALS AND METHODS: A total of 413 consecutive stage II-IVb NPC patients treated with concurrent chemoradiotherapy (CCRT) were enrolled. The overall survival (OS), progression-free survival (PFS), and distant metastasis-free survival (DMFS) were calculated with the Kaplan-Meier method, and differences were compared using the log-rank test. RESULTS: A minimum (mini)-absolute lymphocyte counts (ALC) of < 390 cells/µL or ALC after 3 months of CCRT (post3m-ALC) < 705 cells/µL was significantly associated with worse outcome than mini-ALC ≥ 390 cells/µL (OS, p=0.002; PFS, p=0.005; DMFS, p=0.004) or post3m-ALC ≥ 705 cells/µL (OS, p < 0.001; PFS, p < 0.001; DMFS, p=0.001). Patients with lymphopenia (mini-ALC < 390 cells/µL and post3m-ALC < 705 cells/µL) had a worse prognosis than those without lymphopenia (mini-ALC ≥ 390 cells/µL and post3m-ALC ≥ 705 cells/µL) (OS, p < 0.001; PFS, p < 0.001; DMFS, p < 0.001). Multivariate analysis revealed that post3m-ALC was an independent prognostic factor for OS (hazard ratio [HR], 1.76; 95% confidence interval [CI], 1.12 to 2.78; p=0.015), PFS (HR, 1.86; 95% CI, 1.23 to 2.82; p=0.003), and DMFS (HR, 1.87; 95% CI, 1.13 to 3.08; p=0.014). Multivariate analysis also revealed that patients with lymphopenia had a high risk of death (HR, 3.79; 95% CI, 1.75 to 8.19; p=0.001), disease progression (HR, 2.93; 95% CI, 1.59 to 5.41; p=0.001), and distant metastasis (HR, 3.89; 95% CI, 1.67 to 9.10; p=0.002). Multivariate analysis performed with time dependent Cox regression demonstrated ALC was an independent prognostic factor for OS (HR, 0.995; 95% CI, 0.991 to 0.999; p=0.025) and PFS (HR, 0.993; 95% CI, 0.988 to 0.998; p=0.006). CONCLUSION: Treatment-related lymphopenia was a poor prognostic factor in NPC patients.