Persons who use illicit drugs are stigmatized in the United States. The conferral of a deviant social status on illicit drug users may serve to discourage use. However, stigmatization may also adversely affect the health of those who use illicit drugs, through exposure to chronic stress such as discrimination and as a barrier to accessing care. We hypothesized that aspects of stigma and discrimination would be associated with mental and physical health among illicit drug users. Using street outreach techniques, 1008 illicit drug users were interviewed about stigma and discrimination related to their drug use, and their health. We measured discrimination related to drug use, alienation, perceived devaluation, and responses to discrimination and stigma. Health measures included mental and physical health measures from the Medical Outcomes Study Short Form-36, depression symptoms from the Center for Epidemiological Studies Depression scale, and a sum of health conditions. In adjusted models, discrimination and alienation were both associated with poorer mental health, and only discrimination was associated with poorer physical health. Angry responses to discrimination and stigma were associated with poorer mental health. The association of stigma and discrimination with poor health among drug users suggests the need for debate on the relative risks and benefits of stigma and discrimination in this context.