Objectives: To describe HIV prevalence and the association between syphilis incidence and sexual and drug injection risk behaviours in a cohort of street recruited injecting drug users (IDUs) in Los Angeles County, between 1994 and 1996. Methods: During the study period, 513 street recruited African-American and Latino IDUs were screened for syphilis and antibodies to HIV. Subjects were administered a risk behaviour survey at baseline and followed up at 6 month intervals for 18 months with repeated interviews and serological screening. Rate ratios were used to examine associations between syphilis incidence and demographic characteristics and risk behaviours. A proportional hazard model was used to identify predictors of syphilis incidence independent of demographic characteristics. Results: 74% of the sample were male, 70% African-American, 30% Latino; and the median age was 43 years. Overall baseline serological prevalence of HIV was 2.5% and of syphilis 5.7%. None of the participants were co-infected for HIV and syphilis at baseline or at any of the 6 month follow ups. Among 390 eligible IDUs retained for analysis of incidence data, the overall syphilis incidence was 26.0 per 1000 person years. Higher syphilis incidence was found for women compared with men (RR=2.70; 95% CI 1.60, 4.55), and for those 44 years of age or younger compared with those 45 years of age and older (RR=2.26; 95% CI 1.25, 4.08). African-Americans were more likely to be syphilis incident cases when compared with Latinos, although the difference did not reach statistical significance (RR=1.27; 95% CI 0.72, 2.23). In bivariate analysis, risk behaviours significantly associated with higher syphilis incidence included injection of cocaine, “speedball” and heroin, “crack” smoking, recency of first injection event, backloading of syringes, injecting with others, exchanging drugs or money for sex, multiple sex partners, and non-heterosexual sexual preference. Variables that significantly predicted syphilis infection at follow up in the multivariate analysis included multiple sex partners (RR=7.8; 95% CI 2.4, 25.0), exchanging money for sex (RR=3.0; 95% CI 0.9, 9.6), and recent initiation to injection drug use (RR=4.6; 95% CI 1.1, 18.8). Conclusion: Syphilis transmission among IDUs in Los Angeles County remains a serious public health concern, particularly among IDUs who engage in trading of sex for money or drugs. Although low, the prevalence of HIV observed in this study constitutes a serious concern because of the potential for expanded HIV transmission in this susceptible population of IDUs with high syphilis incidence. Enhanced case finding screening efforts and prevention of transmission of sexually transmitted infections should specifically target hard to reach IDUs and their sexual partners.