Introduction: The human immunodeficiency virus (HIV) and syphilis co-infection is highly common, especially in Brazil, which recorded a high number of cases in 2020. Due to its high prevalence and morbidity, this study aimed to determine the frequency and the clinical-epidemiological profile of HIV and syphilis co-infection between genders in specialized care services in Northeast Brazil. Methods: An analytical cross-sectional study was conducted with secondary data from 171 individuals with HIV and syphilis co-infection. Data were collected in a reference center for acquired immunodeficiency syndrome (AIDS) in Northeast Brazil from 2015 to 2020. Welch’s test compared the means of independent samples; the chi-square and Fisher’s exact test assessed the association between categoric variables. The significance level was set at 5%. This study has ethical approval. Results: The HIV and syphilis co-infection frequency was 15.4%. Individuals with co-infection had a mean age of 34.2 (± 11.0) years and were predominantly men. The women sample started their sex life earlier, had a lower education level and per capita family income, used more illicit drugs, and were mostly heterosexual, married or in a stable union, and unemployed. Men had more anal sex. Moreover, most individuals had syphilis in the asymptomatic phase and HIV with undetectable viral load; CD4 T cells were greater than 350 cells/mm³. Conclusion: The high prevalence of HIV and syphilis co-infection in specialized care services, especially in MSM, highlights the need to improve counseling to reduce sexual risk behavior and improve prevention and care strategies to control these diseases.