Purpose Race and HIV are intertwined in complex ways. African Americans, particularly those residing in the southern United States, are at great risk for contracting and subsequently transmitting HIV. Research on the extent to which members of this population understand the risks associated with engaging in specific behaviors is limited. This paper examines HIV knowledge among at-risk adult African American men and women and the factors associated with levels of HIV knowledge. Methods Based on a conceptual model derived from Social Disorganization Theory and Syndemics Theory, interviews were conducted between 2009 and 2011. Questionnaire-based interviews were conducted with 1,864 respondents from 80 strategically-chosen census block groups in Atlanta, Georgia. An innovative approach to assessing amount of HIV knowledge was implemented, to derive better estimates of the extent of knowledge. Results Overall, HIV knowledge was low (average=43.5% correct answers). Seven factors were identified as contributing uniquely to having higher levels of knowledge about HIV transmission: (1) younger age, (2) being educated beyond the high school level, (3) being gay, lesbian or bisexual, (4) experiencing sexual abuse during childhood and/or adolescence, (5) drinking alcohol less frequently, (6) knowing a larger number of HIV-infected persons and (7) knowing anyone currently living with “full blown” AIDS. Conclusion HIV educational and intervention programs targeting at-risk African American adults need to develop effective ways of bolstering a solid understanding of how HIV is/not transmitted. In particular, efforts need to be targeted toward older adults, those with lower levels of educational attainment and persons who are not acquainted with anyone who is HIV-infected.