Background: Treponema pallidum, the agent causing syphilis, is transmitted through contact with infectious lesions, bodily fluids, blood transfusions, or perinatally. Human immunodeficiency virus (HIV) infection can mask the clinical manifestations of syphilis, while syphilis may exacerbate HIV progression. This study aimed to analyze risk factors associated with HIV co-infection among patients with syphilis. Methods: This retrospective, analytical, observational study reviewed medical records from the Dermatology and Venereology outpatient clinic at Dr. Moewardi Hospital, Surakarta, Indonesia, between January 2018 and December 2022. Demographic, behavioral, and clinical variables were extracted. Univariable analysis was performed using simple binary logistic regression to estimate odds ratios (ORs) with 95% confidence intervals (CIs). Variables with a univariable p-value < 0.25 were entered into a multivariable binary logistic regression model to obtain adjusted odds ratios (aOR). Multicollinearity was assessed using variance inflation factors. Results: A total of 64 newly diagnosed syphilis patients were included; 21 (32.8%) were co-infected with HIV. In univariable analysis, male sex, non-heterosexual orientation, secondary-stage syphilis, and the presence of cutaneous manifestations were significantly associated with HIV co-infection. In the multivariable model, non-heterosexual orientation (OR 8.94, 95% CI 1.78–44.90; p = 0.008) and secondary-stage syphilis (aOR 5.87, 95% CI 1.42–24.21; p = 0.014) remained as independent risk factors. Conclusion: Non-heterosexual orientation and secondary-stage syphilis were independently associated with HIV co-infection among syphilis patients in this Indonesian cohort. The findings support routine integration of HIV screening into the syphilis diagnostic workup, with vigilance for non-heterosexual men and patients presenting with secondary-stage cutaneous disease.