Background: Globally, an estimated 4 million of the 35 million people living with HIV are between the ages of 15 and 24. Nigeria has the second largest burden of HIV worldwide with an estimated 3.2 million individuals living with HIV/AIDS. The prevalence of HIV among adolescents in Nigeria is 3.5%, which is the highest among countries in West and Central Africa. Although insufficient or a complete lack of knowledge about HIV has been identified as a major barrier to HIV prevention efforts, no study has been conducted to evaluate HIV knowledge, identify deficiencies in knowledge, or examine the relationship between HIV knowledge and risky sexual behaviors (RSB) among adolescents in senior secondary school (high school) in Nigeria. Objectives: The purpose of this study was to evaluate HIV knowledge, identify deficiencies in knowledge, and examine the relationship between HIV knowledge and RSB among adolescents in senior secondary schools (high schools) in Nigeria. Patients and Methods: We conducted a cross-sectional survey with a stratified random sample of 361 adolescents from nine senior secondary schools (SS) in Jos Plateau state Nigeria. We used the HIV-KQ-18 survey questionnaire to assess HIV related knowledge and RSB was assessed using the Brief HIV Screener (BHS) questionnaire. Descriptive statistics including mean and standard deviation and multiple linear regression were performed using the SPSS 21. Significance for the statistical test was set at P < 0.05. Results: Overall, 361 participants completed the survey. Forty-seven percent were males and 53% were females with a mean age of 16.9. HIV knowledge (t = -3.3, P < 0.01), age (t = 3.4, P < 0.01) and gender (t = -2.3, P < 0.01) were identified as significant predictors of RSB with female participants having lower RSB scores. An inverse relationship was identified between HIV knowledge and RSB, while a positive relationship existed between RSB and age. Deficiencies in HIV knowledge and misconception about HIV transmission were identified. Conclusions: Adolescents in this study with higher HIV knowledge had low RSB, indicating the importance of including interventions to increase HIV knowledge in HIV prevention programs. Misconceptions about casual means of HIV transmission need to be clarified, and culturally stigmatizing myths about HIV transmission need to be debunked among adolescents in Nigeria.