In order to provide guidance for clinical use of four-dimensional cone-beam CT (4D CBCT), the accuracy of image registration and its influencing factors were analyzed using the automatic registration method when 4D CBCT was used as an image guidance strategy for patients with chest tumors. The respiratory motion model and two kinds of lung plug-ins were used to simulate two types of tumors and their movements in the chest. 4D CT was scanned for each kind of simulated tumor, and 4D CBCT was scanned under various artificial positioning errors. For the registration of 4D CBCT, the manual and automatic registration methods were used for each group. There were more obvious mismatches in the intrapulmonary adhesion tumor group. When the masks were created based on the size of the target area or expanding the target area by 0.5 cm, the results between the automatic registration and manual registration were statistically different. There were no significant mismatches in the isolated lung tumor group, and there was no statistical difference between the results of automatic registration and manual registration. When 4D CBCT is used as an image guidance strategy for patients with chest tumors, the automatic registration procedure should not be used for tumors adhering to chest wall and mediastinum. For solitary lung tumors, the automatic registration method and the manual registration method have similar registration accuracy, but significant mismatches need to be excluded.