This study assessed 1,144 Brazilian injecting drug users (IDUs) recruited on the street through outreach syringe exchange programs by two multi-center cross-sectional studies: 287 IDUs were recruited during the AjUDE-Brasil I Project and 857 during the AjUDE-Brasil II Project. IDU characteristics related to drug use and sexual behavior, and legal and health conditions for the two studies were compared, using decision tree and logistic regression for each individual study, with HIV infection as the outcome. Fifty-two percent of IDUs were HIV-infected in AjUDE I versus 36.5% in AjUDE II. In both studies, HIV infection was independently associated with: mean background HIV prevalence for each site (OR = 2.17; 10.66), HCV seropositive status (OR = 19.79; 15.48), and men who reported ever having sex with other men (OR = 2.10; 2.09). Incarceration (OR = 1.41) and 8 or more years of injecting drug (OR = 2.13) were also associated with HIV in AjUDE II. The high HIV infection rates and high prevalence of both parenteral and sexual risk behaviors in the context of syringe-exchange programs are of great concern and demand thorough surveillance and renewed prevention strategies.