The rates of syphilis and viral co-infections among people who use crack-cocaine (PWUCC) were assessed in this study. This cross-sectional study relied on biological and self-reported socio-behavioral data from a convenience sample of 990 PWUCC from twenty-six municipalities in the states of Amapá and Pará, northern Brazil. Blood samples were collected to assess the presence of Treponema pallidum using the Rapid Qualitative Test (RQT) and the Venereal Disease Research Laboratory (VDRL). Reactive samples by RQT were used to assess the presence of HBV, HCV, and HIV-1 using Enzyme Immunoassay (EIA) and Polymerase Chain Reaction (PCR). Logistic regression models were used to determine the association of variables assessed with syphilis. In total, 287 (29.0%) of the PWUCC sample had reactive results for syphilis. HBV (15.7%), HCV (5.9%), and HIV-1 (9.8%) were detected among PWUCC with syphilis. Young age, low monthly income and education level, long duration of crack-cocaine use, condomless sex, multiple sex partners, and exchange of sex for money/drugs were associated with syphilis. The present study provides unique insights on the epidemiological status of syphilis among PWUCC in northern Brazil, with multiple implications for improving urgent interventions for diagnosis, prevention, and treatment.