Background: Hepatitis C infection is growing threat and major burden on public health, worldwide prevalence of hepatitis C is 3% (170 million infected people). Approximately 10 million people are infected in Pakistan and prevalence is expected to be higher in remote areas. The aim of this study is to assess knowledge, attitude and practice of adolescents towards hepatitis C in Quetta Pakistan. Methods: A cross sectional descriptive study carried out from February 2013 till April 2013. Sample size of this study was 456 and method of sampling was four stage cluster sampling. Samples were randomly selected from 12 schools in urban and semi-urban parts of district Quetta. Equal number of participants were selected (228 Male and 228 Female) from urban and semi-urban settings. Close ended questionnaire was designed, checked and used to access knowledge, attitude and practice of the participants towards hepatitis C infection Results: Response rate of this survey was 100 % and mean number of "Yes" answers to knowledge, attitude and practice questions were 51%, 46% and 42% respectively. The respondent's in urban setting has two times (1.92 odds) higher knowledge, positive attitude and practice than semi-urban participants. Furthermore the respondent's in higher educational level has two times (1.7 odds) better knowledge, positive attitude and practice than lower educational level participants. Furthermore this study indicates to reveal some evidence of stigmatization being exhibited by participants in both setting. Higher level of school education (group III) and older age (group III) respondents in both setting has positive attitudes toward hepatitis C than lower level of education (group I) and younger age (group I). In addition it is observed that adolescents by growing age and entering higher education group are getting more knowledge and positive attitude and practice about hepatitis C disease and it's a positive trend. Conclusions: This study observed that knowledge, positive attitudes and practices towards hepatitis C among adolescents was partial in both setting. There are some important gaps need to be strengthened especially in semiurban setting and female group of participants. The results of study indicate that there is lack of understanding about infection control and prevention of hepatitis C among study participants. Thus there is need of critical level of public awareness in district Quetta, especially among adolescents, to decrease burden of hepatitis C infection. Extensive health education campaigns about hepatitis C are beneficial for adolescents, particularly to residents of semi-urban and rural areas.