Numerous guidelines have been issued by Public Health institutions and related authorities in the last few years for the prevention of HIV infection among occupationally exposed workers. Our study was aimed at comparing the regulations and guidelines on this topic that have recently been adopted by Western countries, also taking into account the impact of the problem in current scientific literature. Health-care workers are the category with the highest risk for occupational exposure to HIV principally associated with accidental needlesticks, skin lesions and percutaneous injuries. In preventive and occupational medicine, Italy, the European Union and the USA have founded their recommendations on universal and specific precautions issued by the Center for Disease Control. Moreover, as long ago as 1990 the Italian Ministry of Health issued official guidelines for the prevention of occupational exposure to bloodborne pathogens. Post-exposure management is crucial for the protection of workers at risk. As a consequence of the failure of some monotherapeutic zidovudine treatments, different countries revised their guidelines and recommended the use of a combination of chemotherapeutic drugs for the post-exposure regimen. However, most of the currently available data are derived from efficacy studies of combined therapy on HIV-infected patients. Therefore, further experimental investigations are needed aimed at evaluating the short- and long-term effects of these treatments in the post-exposure protection of workers at risk for HIV infection.