Abstract: Objective To observe the effect of ceftriaxone sodium combined with benzathine penicillin in the treatment of patients with secondary syphilis. Methods Eighty patients with secondary syphilis admitted in our hospital were selected and randomly divided into control group and study group. The control group was treated with benzathine penicillin, and the study group was treated with ceftriaxone sodium and benzathine penicillin. The efficacy was compared between the two groups. Results The total effective rate of the study group was 97.50%, which was significantly higher than 75.00% of the control group(P<0.05). The negative conversion rates of toluidine red unheated serum test(TRUST)in the study group were significantly higher than those in the control group at 30, 60 and 90 days after treatment(P<0.05). The remission time of skin lesions in the study group was significantly shorter than that in the control group(P<0.05). After treatment, the improvement of peripheral blood T lymphocyte subsets such as CD3⁺, CD4⁺, CD8⁺ and CD4⁺/CD8⁺ in the study group was significantly better than that in the control group(P<0.05). Conclusion Ceftriaxone sodium combined with benzathine penicillin is effective in the treatment of patients with secondary syphilis, which can increase the clinical efficacy and promote the regression of skin lesions.