The study aimed to investigate the difference of setup errors on different registration in the treatment of nasopharyngeal carcinoma based on weekly cone-beam computed tomography (CBCT). Thirty nasopharyngeal cancer patients scheduled to undergo intensity-modulated radiotherapy (IMRT) were prospectively enrolled in the study. Each patient had a weekly CBCT before radiation therapy. In the entire study, 201 CBCT scans were obtained. The scans were registered to the planning CT to determine the difference of setup errors on different registration sites. Different registration sites were represented by bony landmarks. Nasal septum and pterygoid process represent head, cervical vertebrae 1-3 represent upper neck, and cervical vertebrae 4-6 represent lower neck. Patient positioning errors were recorded in the right-left (RL), superior-inferior (SI), and anterior-posterior (AP) directions over the course of radiotherapy. Planning target volume margins were calculated from the systematic and random errors. In this study, we can make a conclusion that there are setup errors in RL, SI, and AP directions of nasopharyngeal carcinoma patients undergoing IMRT. In addition, the head and neck setup error has the difference, with statistical significance, while patient setup error of neck is greater than that of head during the course of radiotherapy. In our institution, we recommend a planning target volume margin of 3.0 mm in RL direction, 1.3 mm in SI direction, and 2.6 mm in AP direction for nasopharyngeal cancer patients undergoing IMRT with weekly CBCT scans.