ABSTRACT Background: A high seroprevalence of various transfusion-transmitted infections (TTIs) in donated blood is the main safety concern, especially in low- and middle-income countries. As per the World Health Organization (WHO) recommendation, all blood donations must be tested for human immunodeficiency virus (HIV), hepatitis B virus (HBV), hepatitis C virus (HCV), Treponema pallidum infection, and malaria, which mainly comprises the major bulk of TTIs. Aims: The purpose of this study is to observe the seroprevalence of hepatitis C virus and Treponema pallidum infection over the period of 5 years in blood donors of our blood center along with their epidemiological determinants with respect to age, sex, residence, occupation, and type of donors Materials and Methods: Retrospective study was conducted for the period of 5 years, from 1st January 2017 to December 2021, estimating the seroprevalence of hepatitis C and Treponema pallidum infection in the blood donors along with their epidemiological determinants Results: Out of 19,689 donations in 5 years, 690 (3.50%) units were positive for transfusion-transmissible infections with 1.67% donors seropositive for HCV, 1.23% for Treponema pallidum infection, 0.42% for HBV, and 0.18% for HIV. The prevalence of TTIs was found to be highest in 2020 (4.52%) and least in 2017 (2.57%). Out of a total of 330 HCV cases detected in 5 years, 84.85% of cases were seen in voluntary donors. Rural donors constituted 71.21% of cases. The majority of cases were seen in the age group of 18–30 years, i.e., 61.82%, and a maximum number of cases were seen in the farmers (31.21%), followed by laborers and construction workers (21.21%). Out of a total of 242 cases of Treponema pallidum infection, 84.29% were seen in voluntary blood donors. Demographic data showed 70.24% of cases in rural donors. Occupational data revealed a maximum number of cases in farmers (34.29%), followed by laborers (21.90%). Conclusion: Higher seroprevalence of HCV and Treponema pallidum infection in our region as compared with other areas is a matter of great concern about the growing infection rate of these in our area. Stringent use of donor selection criteria and more vigorous donor screening is utmost need of the hour for reducing the burden of TTIs in blood transfusion services.