HIV/AIDS is recognized as a national priority health issue in Ghana. Consequently, the Ghana AIDS Commission and the National AIDS Control Programme were established, among other things, to enhance the knowledge and awareness on the nature, causes, effects and means of managing the spread of HIV/AIDS among populations at risk in Ghana. Through the efforts of these bodies and other stakeholders in health, several awareness creation and sensitization efforts have been targeted at teenage girls, a high risk group in Ghana. This study therefore assesses the knowledge and awareness of HIV/AIDS among senior high school girls in their teens in Ghana using a sample of 260 female students of West African Senior High School. The data collected were analyzed and discussed under relevant themes and within the context of the literature. The study revealed that generally, senior high school girls were knowledgeable on the nature, modes of transmission, and prevention of HIV/AIDS. There were however some students who exhibited limited knowledge on some issues including the spiritual causes and treatment of HIV/AIDS, contacts and associations with infected persons, as well as determination of HIV infection from appearances rather than testing. The study also raised important concerns about the reluctance of senior high school girls to use condoms as a preventive measure and the need to reorient HIV/AIDS awareness interventions in Ghana.