We conducted a retrospective analysis of data from a prospective nPEP (non-Occupational Post Exposure Prophylaxis) registry based on patients consulting at one academic Emergency department located in Brussels, Belgium. We review here 1,357 cases consulting from January 2011 to December 2013.The objective of the study is to determine whether emergency physicians prescribe nPEP according to national guideline with support from IDS (infectious disease specialists). As this intervention has a high cost we wanted to verify correct allocation of treatment to high risk patients. Moreover we wanted to determine whether compliance to nPEP when prescribed by an Emergency Physician was different from literature reports. Finally we wanted to describe the population consulting for nPEP at our center. Emergency physicians prescribed nPEP more frequently in high risk exposures (98.6%) compared to intermediate risk exposures (53.2%); adequately allocating resources from a public health perspective. Appropriateness of prescription when evaluated according to nPEP Belgian guidelines was 98.8%.Compliance with nPEP prescribed by Emergency physicians was 60% in our study. Compliance was the highest in MSM (Men who have Sex with Men) while sexual assault victims showed the lowest compliance. Altogether this study suggests that Emergency physicians can safely and adequately prescribe nPEP when supported by a comprehensive guideline. Recognizing intrinsic differences within heterogeneous populations consulting for nPEP may improve compliance to this high-cost public health intervention.