Background: Syphilis has reemerged as a global health concern. Per the US Centers for Disease Control and Prevention guidelines, physicians should re-test patients on the date of syphilis treatment. We evaluated the change in syphilis rapid plasma reagin titer from the date of a reactive screening test to the date of treatment. Methods: In an ongoing clinical trial of the effectiveness of cefixime in participants with and without HIV infection we screened patients for syphilis utilizing historical and screening rapid plasma reagin (RPR) titers. Participants titers were repeated on the day of treatment as the baseline for study outcomes. We compared RPR titer results from study participants on the day of initial diagnosis and the day of treatment. Percentages of participants with two-fold or greater titer changes were calculated. We categorized results by the time interval between titers Results: As of January 5th, 2023, we enrolled 56 participants. The median duration between the day of diagnosis and day of treatment is 7 (range 0-90) days. Among participants with 0-6 days between diagnosis and treatment, 15.4% (8/13) had an increased RPR and 46.2% (6/13) had a decreased RPR. Among participants with 7-14 days between diagnosis and treatment 29.0% (9/31) had an RPR increase and 35.5% (11/31) had an RPR decrease. In cases with 14+ days between diagnosis and treatment, 22.2% (2/9) and 44.4% (4/9) had increases and decreases, respectively. Fifteen (44.1%) of the 34 participants with changed titers had 4-fold or higher titer changes. Conclusion: Our results support repeat RPR titer testing the day of treatment for patients with syphilis. Repeat testing may help avoid treatment response misinterpretation due to changes in titers that occur between the time of diagnosis and the time of treatment. [ABSTRACT FROM AUTHOR]