Worldwide, 500 million people a year acquire a sexually transmitted disease (STD). Adolescents, accounting for 25% of the sexually active population, are the most affected. To analyze sexual behavior among Italian adolescents and their knowledge of STDs, with the goal of preventing their transmission, a questionnaire was administered to 2867 secondary school students (1271 males and 1596 females) aged 14-21 years. For the study, 1492 students were interviewed in Genoa (Northern Italy) and 1375 in Lecce (Southern Italy). For 37% of the respondents, parents and teachers were the main source of information on sex, and 95% believed that school should play the primary role in sex education. However, only 9% considered the sex education they received in school good. Noteworthy, only 0.5% of the teenagers recognized the sexually transmitted diseases from a list of diseases, and 54% of them did not know what a Pap test was. Confusion about the meaning of contraception and prevention was evident; only 22% knew that condoms and abstinence are the only methods for preventing STDs. Finally, a consistent number of students are exposed to risk factors for STDs transmission; e.g., alcohol and recreational drug use, promiscuity and improper condom use. On the basis of our study, there is an urgent need for the introduction of sex education as a proper subject in Italian schools.