BACKGROUND Chemotherapy, target therapy, and immunotherapy are increasingly being used in the systematic treatment of nasopharyngeal carcinoma (NPC), during which the occurrence of hepatitis B virus (HBV) reactivation might increase. However, data regarding HBV screening and reactivation and the clinical management of NPC patients with HBV infections are lacking. This study was aimed at clarifying the risk of reactivation for NPC patients on different regimens while providing evidence concerning HBV screening and management in an endemic area. METHODS With the NPC database from an established big‐data intelligence platform at Sun Yat‐Sen University Cancer Center in China, NPC patients who were diagnosed between 2008 and 2016 and underwent HBV screening and regular monitoring of liver enzymes and HBV deoxyribonucleic acid (DNA) were analyzed. RESULTS Among the 46,919 patients identified, the HBV screening rate was 24.8% (11,616 of 46,919). Among the screened patients with an HBV infection, regular monitoring of liver enzymes and HBV DNA occurred for 563 patients. The incidence of HBV reactivation and HBV‐related hepatitis was 9.1% (51 of 563) and 2.5% (14 of 563), respectively. The reactivation risk varied for different treatments and regimens and ranged from 0.0% to 21.4%. Detectable baseline HBV DNA (odds ratio OR, 2.93; P < .01), the presence of liver metastasis at diagnosis (OR, 7.19; P < .01), and antiviral prophylaxis (OR, 0.29; P < .01) were significantly associated with reactivation. CONCLUSIONS In NPC patients with chronic HBV infections on high‐risk regimens, the reactivation risk is similar to or exceeds the risk associated with other immunosuppressive therapies for which screening and prophylaxis are recommended. Our findings, therefore, support HBV screening and prophylaxis for these patients, whereas regular monitoring might be appropriate for patients with resolved HBV infections or those receiving low‐risk regimens. Cancer 2017;123:3540‐9. © 2017 American Cancer Society. Data regarding hepatitis B virus screening and reactivation and the clinical management of nasopharyngeal carcinoma patients with hepatitis B virus infections are lacking. This study clarifies the risk of hepatitis B virus reactivation with different regimens, systematically investigates the benefit of hepatitis B virus screening and antiviral prophylaxis, and identifies the risk factors associated with reactivation in patients with nasopharyngeal carcinoma.