Background: Despite the increasing number of syphilis cases, there has been a considerable lack of recent data comparing the efficacy and duration of benzathine penicillin G, ceftriaxone, and tetracycline in Korean patients. Objective: To compare the efficacy and duration of benzathine penicillin, ceftriaxone, and tetracycline in Korean patients with syphilis. Methods: We retrospectively reviewed 145 cases of syphilis from 2004 to 2019 and statistically analyzed the treatment efficacy and duration. Results: Patients in the benzathine penicillin, ceftriaxone, and tetracycline treatment groups showed no significant statistical difference in terms of treatment rate (chi-square test, p=0.962). Similarly, treatment duration among groups was not statistically significant (one-way analysis of variance, p=0.792). Co-infection with human immunodeficiency virus resulted in reduced treatment rate (p=0.016) and increased treatment duration (p=0.007). Conclusion: This retrospective study showed no significant difference between penicillin, ceftriaxone, and tetracycline in terms of treatment rate and duration. However, a difference in treatment rate and duration was evident between the non-infection and HIV co-infection groups.ng