Introduction: Transfusion of blood and its components is a life saving measure in various medical and surgical emergencies. Transfusion carries the risk of transmitting the life threatening transfusion transmissible infections (TTIs) agents like Human immunodeficiency virus (HIV), Hepatitis B Virus (HBV), Hepatitis C Virus (HCV), Syphilis and Malaria. Aim & Objectives: To estimate the prevalence of Major Transfusion-Transmissible Infections among Blood Donors at a rural tertiary healthcare teaching hospital of North India. Materials and Methods: The present study was conducted on 7405 blood donors who donated blood in the Blood Transfusion Department, BPS Government medical college for women, Khanpur Kalan, Sonipat over a period of one year. For testing purpose, ELISA kits of 4th generation for HIV І & ІІ, while 3rd generation kits for HBsAg and HCV were used. Syphilis antigen was screened by Anti-TP Test and malaria was screened by the Pan Antigen Card Test. Results: Amongst a total of 7405 donors, 7235 (97.7%) were male donors and only 170 were (2.3%) female donors. There were 6987 (95.3%) voluntary donors whereas 418 (5.7%) replacement donors. The overall seroprevalence of 2.84 % (211 cases of TTI in 7405 donors) was observed. The prevalence of HIV, HBsAg, HCV, Syphilis and Malaria are 0.06%, 1.18%, 1.02%, 0.56% and 0% respectively. Conclusion: Voluntary donations are safer as compared to replacement ones and should be encouraged. Proper efforts in planned way should be made to increase the number of voluntary donors with a target of 100% and reduce replacement donations to a minimum.