Among adolescents in Africa and in the rest of the world, unprotected sexual intercourse is the primary cause of HIV transmission. There is limited information on population based study of adolescents who are not-in-school. A quantitative and qualitative study was conducted among adolescents aged 10-19 (n = 483, mean age = 16.6) in the Ashanti region of Ghana on sexual behavior, condom use, and peer norms regarding sexuality. Age of sexual debut was younger for those in-school. However, out-of-school adolescents were more likely to ever have sexual intercourse (72.2% vs. 27.8%) and use condoms (83.6% vs. 16.4%) compared to their in-school counterparts. Religious affiliation was associated with being less sexually active. Statistically significant differences occurred for condom use and increased sexual activity with age. There is the need for programs to increase condom use. Adolescents in Ghana represent a vulnerable population and concerted efforts must be made to reach them.