The goal of this study was to compare HIV risk behaviors of amphetamine and non-amphetamine injectors at syringe exchange programs (SEP) in the United States and to identify factors associated with injection risk. This analysis is based on data from a random cross-section of participants at 13 SEPs in different parts of the country. All interviews were done using Audio Computer-Assisted Personal Interviewing technology. Amphetamine injectors differ from other SEP participants in that they are younger and more likely to be White, to have had a recent same sex partner, and to be homeless. Rates of injection risk behavior are higher among amphetamine injectors than other SEP participants, but rates of condom use are similar. Factors associated with injection risk behavior are amphetamine injection, homelessness, depression, and having a recent same-gender sexual partner (for both men and women). SEPs have been repeatedly demonstrated to reduce injection risk behavior, but some groups of program participants continue to be at elevated risk. SEPs may need to develop new approaches to outreach and education to address the needs of amphetamine injectors and other populations at persistent risk.