Background: Premarital sex is any sexual activities with an opposite sex partners or a same sex before he/she has started a marriage life. The term is usually used to refer the inter course before the legal age of marriage. In the course of experimentation, adolescents often in counter high risk situation, as contracting STD /HIV/AIDS and often exposed to un intended pregnancy and illicit abortions. Objective: This study was conducted to assess knowledge, attitude and practice towards premarital sex and HIV/AIDS among students who are attending in MizanTepi University. Methods: A cross sectional study was conducted from April 08-September, 08, 2014-in MTU, Mizan campus regular students. Stratified sampling technique were used after making strata based on Collage and sex proportion. This study using systemic random sampling. Data were collected by three Public Health interns, using self-administrated questionnaires. Students from each Collage were being explained about the objective and confidentiality of the study while distributing and collecting the questionnaires. Results: A total of 372 participants, 254(68%) were males and 118(32%) were females. All of the students know what cause HIV/AIDS; majority of them knew major transmission routes. Sexual transmission mentioned as a major routes transmission in our study by 281(75.5%) of students but knowledge was translated into practice as 133(35.6%) approved premarital sex and practiced it. Conclusion and Recommendation: The study participants have good knowledge of HIV/AIDS related to its cause, routes of transmission and also about preventive mechanism by this knowledge was not practiced. The study participants were citing religion as reason for not having premarital sex and this should include in their day to day teachings. The HIV/AIDS agenda should an agenda for everyone and families should discuss with the adolescents and adults.