The objective of this study was to assess the HIV/AIDS gender differences in awareness and knowledge among rural high school students outside the Mthatha Municipality, Eastern Cape Province, South Africa. The sample of the study comprised 83 female and 62 male participants making a sum of 145 students selected from a rural high school. Their age ranged from 15 to 25 years, with a mean of 19.3 years. Participants were administered a 15-questions/statements HIV/AIDS questionnaire. The method of data analysis comprised frequencies, percentage and chi-square. The results showed that there were three categories in the findings. In the first category for some questions, there were no gender differences. In the second category, there were gender differences in favour of male participants, while in the third category girls were more knowledgeable. In conclusion, it was advocated that, educating, motivating, persuading and enabling should be the chief cornerstone of HIV/AIDS public education campaigns. This will go a long way in equipping rural secondary school girls and boys to protect themselves against the scourge of HIV/AIDS

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