Adolescents are tomorrow's adults and make up to 16% of the world's entire population. Caring about their reproductive health is both a mission and an obligation for all healthcare institutions and the community as a whole. The aim of this study was to examine sexual behavior, knowledge and the use of contraception, as well as the source of information on the topic, among high school students in Niš and Preševo. An anonymous survey was conducted among 710 highschool students in Niš and 215 in Preševo in December 2017. It consisted of 13 questions about sexual activity, knowledge and the use of contraceptive methods. The average age of the respondents was 17.2 ± 0.5 years. 31.5% of high school students from Niš had sexual intercourse, for the first time with 16.2 ± 1.1 years of age and 23.2 high school students from Preševo with 15.7 ± 1.1 years of age. Male students engaged significantly more often in sexual intercourse in comparison to their female counterparts. Students of both sexes and from both cities most frequently cited love as the reason for having sexual intercourse. The incidence of the regular use of contraception was statistically higher in Niš as opposed to Preševo (p = 0.007) while being equal between the sexes (p = 0.738). The most used method of contraception during both first and last intercourse in both cities and both sexes was a condom. The majority of respondents from Niš (83.5%) and Preševo (93.2%) did not ask for professional advice. Female students asked for professional advice more often than male students. The Internet was the most frequent tool for gathering information about contraception in both cities (Niš 61.2%, Preševo 55.0%) and with both sexes (male 64.9%, female 51.2%). Two most common reasons for the use of contraception were protection from unwanted pregnancies (Niš 59.6%, Preševo 71.2%) and protection from sexually transmitted diseases (Niš 48.3%, Preševo 16.6%). It is necessary to plan a long term strategy for sexual education with relevant information in both cities, in a manner appropriate for adolescents, while acknowledging the important role of the Internet in informing adolescent about this topic.