American Indians and Alaska Natives have had low employment in recent history. Drug users also have low employment due to cycles of drug use and relapse,and the impact of the type of drug abused on levels of functioning. Drug use is associated with increased HIV risk through injection drug use, frequency of injection, and needle sharing. Data from three sites of the NIDA Cooperative Agreement for Community Based-Outreach/Intervention Research were analyzed to determine the relationship among race/ethnicity, age, and level of educational attainment on employment and unemployment at intake interview and six-month follow-up. HIV risk for those employed and unemployed was then assessed. American Indian and Alaska Native drug users were younger, less educated, and less likely to have a paid job at both intake and follow-up than non-Native drug users. Those participants who were unemployed at baseline interview who were American Indian/Alaska Native were less likely to transition to employment at six-month follow-up than other race/ethnicity groups in the cohort. However, all participants showed low levels of employment at follow-up. Individuals who were employed at baseline and those who transitioned to employment had lower levels of injection drug use and needle sharing than those who were unemployed at both baseline and follow-up. American Indian and Alaska Native drug users may be at risk for acquisition of HIV due to drug risk behaviors that appear to be associated with unemployment.