Cost-benefit management trends in Taiwan healthcare settings have led nurses to perform more invasive skills, such as Port-A cath administration of medications. Accordingly, nurses must be well-prepared prior to teaching by the mentor and supervision method. The purpose of the current study was to develop a computer-assisted protocol using virtual reality (VR) in performing Port-A cath as a training program for novice nurses. A pre-tested and post-tested control group experimental design was used in this study. Seventy-seven novice nurses were invited from one large medical center hospital in North Taiwan. Thirty-seven and forty nurses were randomly assigned to experimental and control groups. First, we designed a 40 minute port-A cath injection VR simulation. Then, the experimental group practiced this simulation two times over 3 weeks. The control group attended the traditional class. The post-test 1 was right after completion of the simulation practice. The post-test 2 was after the second simulation practice in 3 weeks. The results showed that most novice nurses lacked Port-A cath experience both in the classroom and during the period of their practice training. The knowledge score regarding the Port-A cath technique was significantly higher in the nurses that participated in the simulation training than in the control group. The novice nurses were most satisfied with the reduction in their fear of performing the Port-A cath technique and their enhanced clinical skills. VR simulation significantly reduced error rates and increased correct equipment selection, showing that nurses who participated in the simulation may be better prepared for inserting Port-A cath.