Purpose: Senior nursing and medical interns’ lack of familiarity and confidence with respect to practicing universal precaution for theprevention of occupational needlestick or sharp injuries may harm themselves. Trainees’ self-reported needlestick or sharp injury ratewas known to be especially high during the first 2 months of internship in Taiwan. This prospective cohort study aimed to assess the effect of newly developed virtual reality (VR) game, which uses Gagne’s learning model to improve universal precaution for needlestickor sharp injury prevention and decrease the rates of needle stick or sharp injuries in new-coming medical and nursing interns in Taiwan. Methods: From 2017 to 2019, the VR system was developed and applied in training of 59 new-coming nursing and 50 medical interns. Occupational needlestick or sharp injury prevention was sought to be achieved through a game of right and wrong choices for safe orunsafe universal precaution behaviors. Results: In comparison with medical interns, a higher proportion of nursing interns had past experiences of deep occupational needlestick or sharp injury. Before VR training, the familiarity and confidence for needlestick or sharp injury prevention were higher amongnursing interns than medical interns. Trainees with past experiences of deep needlestick or sharp injury exhibited better performanceon the accuracy rate and time needed to complete 20 decisions than those without past experiences in VR practice. All trainees showedan improved performance after VR training. A high proportion of trainees reported that the VR-based training significantly decreasedtheir anxiety about needlestick or sharp injury prevention. Conclusion: This self-developed VR game system using Gagne’s flow improved universal precaution for needlestick or sharp injuryprevention and reduced the needlestick or sharp injury rates in the first 2 months of nursing and medical internship.