Ethiopia is faced with an increasing problem from HIV infection, and the vulnerability of adolescents is a key concern. There is little information on the knowledge, attitudes and practices of this age group with respect to HIV, sexually transmitted diseases and preventive measures. We conducted a cross-sectional study among 260 students from two rural high schools in North Western Ethiopia. We found that although the general awareness of HIV was high, correct knowledge of the virus and its modes of transmission was shown in only 44% of adolescent boys and 41% of adolescent girls. Knowledge of HIV and condoms was lower among students whose parents were farmers, significant so among girls (p=0.02). Use of condoms among sexually active single male students (49%) was insufficient but was higher than among adolescents in many other African settings. Knowledge of STDs was generally low: 82% of adolescent males and 37% of adolescent females had some awareness of STDs. Almost 20% of sexually active males in the study had previously experienced an STD, almost all of whom had visited a commercial sex worker. Targeted interventions are warranted among adolescents and sex workers in Ethiopia complemented by STD treatment services.