Objectives: To analyze the number, epidemiology and circumstances of needlestick and sharps injuries (NSSI) and exposures to body fluids and to identify further preventive measures to improve the occupational safety of health care workers (HCW). Material and Methods: Setting: German university tertiary-care referral center. Retrospective study based on injury documentation sheets of the hospital’s staff and faculty health service and, if given, on reports by continuity doctors and by the accident and emergency department in January 2014–June 2016. Results: Altogether, 567 injuries were registered with a significant decrease of cases over the study period. The majority of accidents occurred in the operating theater (35%). Stress, time pressure, overstrain, carelessness and distraction were found to be the main reasons for injuries. At least 30% of the cases were preventable, mainly by wearing personal protective equipment (PPE), by proper disposal of an item and by early replacement of overfilled sharps containers (SC). In 20% of the cases involving an item, the injury was caused by a safety-engineered device (SED). Almost one-third of these injuries were attributable to an improper use of the SED. Conclusions: Despite many efforts made to reduce their number, NSSI still occur. Health care workers and students should be offered regular trainings to be sensitized to this topic and to learn the appropriate use of SED. Moreover, organizational measures must be taken, such as the provision of suitable PPE and safe SC. Strategies need to be established to improve the working conditions and reduce the stress level of HCW. Int J Occup Med Environ Health. 2022;35(4):497–507