The objectives of the study were to study the seroprevalence of hepatitis B virus (HBV) and hepatitis C virus (HCV) infections among health college students (HS) and health care workers (HCWs) in the Najran Region of south-western Saudi Arabia and to study the students' knowledge of occupational exposure to blood-borne viral infections. METHODS: A cross-sectional study of a representative sample of 300 HS and 300 HCWs was conducted. RESULTS: An overall seroprevalence of HBV of 1.7% and 8.7% was found among HS and HCWs, respectively. Two-thirds of HS (66.7%, 200) and 23.3% (70) of HCWs lack anti-HBs and are susceptible to HBV infection. An overall seroprevalence of HCV of 0% and 0.3% was found among the HS and HCWs, respectively. The present study indicates poor knowledge among HS and moderate knowledge among HCWs regarding occupationally transmitted blood-borne diseases, safe injection practices, and standard precautions to prevent occupationally transmitted blood-borne infections. CONCLUSION: It is mandatory to develop a structured program to raise awareness among HS, and current health colleges' curricula should be upgraded to address these issues early. The HS should be considered new recruits to health services in terms of their initial screening for blood-borne infections and vaccination against HBV. The development of a novel continuing medical education and pre-employment awareness program for HCWs is recommended to address the following: blood-borne diseases transmitted occupationally, standard precautions to prevent occupationally transmitted blood borne infections, and safe injection practices.