This study investigates the differences in peripheral blood parameters between patients with non-neurosyphilis and neurosyphilis, aiming to identify potential serum biomarkers to predict the occurrence of neurosyphilis and avoid unnecessary lumbar punctures. A retrospective analysis was conducted on 110 HIV-negative syphilis patients in this study. We found that the serum homocysteine (Hcy) levels in the non-neurosyphilis group, asymptomatic neurosyphilis group, and symptomatic neurosyphilis group were 12.30 (10.45, 13.25), 17.50 (12.03, 26.28), and 15.70 (13.70, 20.20), respectively. The serum Hcy levels in the asymptomatic neurosyphilis group and symptomatic neurosyphilis group were significantly higher than those in the non-neurosyphilis group (P<
0.05). The AUC for serum Hcy in diagnosing neurosyphilis was 0.861 (95% CI: 0.715-0.950), with a sensitivity and specificity of 98.47% and 71.43% respectively. The study indicated that serum Hcy levels serve as a potential biomarker to differentiate neurosyphilis from non-neurosyphilis.