Background and Objectives: An increasing prevalence of sexually transmitted infections especially Syphilis in blood donors may lead to increased donor deferrals and lessen the donor pool. Hence it is the need of the hour to device a structured screening methodology for Syphilis reactive donors. The aim of the study is to estimate the prevalence of syphilis in blood donors and to estimate the response rate of notified blood donors. Patients and Methods: This was a retrospective study, conducted in a Blood Centre (BC) on the blood donors visiting for donation from January 2020 to September 2021. The donors screened positive on chemiluminescence immunoassay were included after informed consent was obtained, and donor demographics and follow-up response rate were analyzed. Frequency and percentages were used to express descriptive statistics and Chi-square was used to test the relationship between categories (p<0.05 considered significant). Results: Out of 26,698 donations during the study period, 133 donors were screened positive for syphilis. 127 (96%) donors consented to postdonation. Out of 127, only 61 were notified regarding the infection and were advised about further followup. 52% of the donors who consented to postdonation counseling were not notified due to erroneous contact details. Out of 46 responders, only 17 underwent further testing. Conclusions: The prevalence rate of syphilis was found to be 0.49%. Among the donors notified, 75% responded back to the BC. Due to social stigma and inadequate knowledge about the disease, often, donors are hesitant to give a reliable exposure history. Adequate education and adapting to a structured screening methodology is the need of the hour to reduce the risk of transfusion-transmitted syphilis.