Respondent-driven sampling (RDS), a chain referral sampling approach, is increasingly used to recruit participants from hard-to-reach populations, such as injection drug users (IDUs). Using RDS, we recruited IDUs in Tijuana and Ciudad (Cd.) Juárez, two Mexican cities bordering San Diego, CA and El Paso, TX, respectively, and compared recruitment dynamics, reported network size, and estimates of HIV and syphilis prevalence. Between February and April 2005, we used RDS to recruit IDUs in Tijuana (15 seeds, 207 recruits) and Cd. Juárez (9 seeds, 197 recruits), Mexico for a cross-sectional study of behavioral and contextual factors associated with HIV, HCV and syphilis infections. All subjects provided informed consent, an anonymous interview, and a venous blood sample for serologic testing of HIV, HCV, HBV (Cd. Juárez only) and syphilis antibody. Log-linear models were used to analyze the association between the state of the recruiter and that of the recruitee in the referral chains, and population estimates of the presence of syphilis antibody were obtained, correcting for biased sampling using RDS-based estimators. Sampling of the targeted 200 recruits per city was achieved rapidly (2 months in Tijuana, 2 weeks in Cd. Juárez). After excluding seeds and missing data, the sample prevalence of HCV, HIV and syphilis were 96.6, 1.9 and 13.5% respectively in Tijuana, and 95.3, 4.1, and 2.7% respectively in Cd. Juárez (where HBV prevalence was 84.7%). Syphilis cases were clustered in recruitment trees. RDS-corrected estimates of syphilis antibody prevalence ranged from 12.8 to 26.8% in Tijuana and from 2.9 to 15.6% in Ciudad Juárez, depending on how recruitment patterns were modeled, and assumptions about how network size affected an individual's probability of being included in the sample. RDS was an effective method to rapidly recruit IDUs in these cities. Although the frequency of HIV was low, syphilis prevalence was high, particularly in Tijuana. RDS-corrected estimates of syphilis prevalence were sensitive to model assumptions, suggesting that further validation of RDS is necessary.