Several recent studies have utilized respondent-driven sampling (RDS) methods to survey hidden populations such as commercial sex-workers, men who have sex with men (MSM) and injection drug users (IDU). Few studies, however, have provided a direct comparison between RDS and other more traditional sampling methods such as venue-based, targeted or time/space sampling. The current study sampled injection drug users in three U.S. cities using RDS and targeted sampling (TS) methods and compared their effectiveness in terms of recruitment efficiency, logistics, and sample demographics. Both methods performed satisfactorily. The targeted method required more staff time per-recruited respondent and had a lower proportion of screened respondents who were eligible than RDS, while RDS respondents were offered higher incentives for participation.