Background <p>The prognosis and its predictors in human immunodeficiency virus (HIV)-negative neurosyphilis remain poorly characterized.</p> Objective <p>To identify clinical, laboratory, and neuroimaging predictors of poor long-term outcomes of HIV-Negative Neurosyphilis.</p> Methods <p>We conducted a retrospective cohort study with prospective follow-up in 128 newly diagnosed HIV-negative neurosyphilis patients at a single tertiary center. Baseline evaluations included clinical profiles, cerebrospinal fluid (CSF) analysis, and brain magnetic resonance imaging (MRI). The primary outcome was a composite poor global outcome (modified Rankin Scale[mRS] &gt; 2, Activities of Daily Living [ADL] &gt; 14, or Informant Questionnaire on Cognitive Decline in the Elderly[IQCODE] &gt; 3.19). Multivariable logistic regression identified independent predictors.</p> Results <p>After a median follow-up of 6.4 years, 40.6% of patients had a poor global outcome and all-cause mortality was 17.2%. Multivariable analysis identified parenchymal neurosyphilis (odds ratio [OR], 19.10; 95% confidence interval [CI], 5.68–64.23), elevated CSF protein (OR, 9.03; 95% CI, 2.31–35.32), and lacunar infarct score (OR, 2.48 per point; 95% CI, 1.44–4.27) as independent predictors of poor outcome. Hypertension predicted mortality (OR, 4.12; 95% CI, 1.50–11.34).</p> Conclusion <p>In HIV-negative neurosyphilis, parenchymal involvement, elevated CSF protein, and lacunar infarct burden are robust predictors of poor global outcomes, while hypertension predicts mortality. These findings support integrated clinical, CSF, and neuroimaging assessments for prognostic stratification and underscore the need for aggressive vascular risk factor management.</p> Clinical trial number <p>Not applicable.</p>