BACKGROUND:Acquisition of transfusion transmissible infections in the process of therapeutic blood transfusion is a major global health challenge in transfusion medicine.This study aimed to determine the prevalence and trends of major transfusion transmissible infections among blood donors.METHOD:A retrospective analysis of consecutive blood donors’ records covering the period between July 2010 and June 2013was conducted at Dire Dawa Blood Bank, Eastern Ethiopia.RESULT: A total of 6376 blood donors were tested, out of which 5647(88.57%) were replacement donors and 729(11.43%) were voluntary donors. The majority of them were male, 5430(85.16%), and aged between 18–32 years, 4492(70.45%). A total of 450(7.06%) donors had serological evidence of infection with at least one pathogen. The overall positivity rates of HBV, HIV, HCV and syphilis were 4.67%, 1.24%, 0.96%, and 0.44% respectively. Trends for transfusion-transmissible infections showed a significant decrease from 9.51% in 2010 to 6.95% in 2013 with the least prevalence in 2012 (5.90%) (P = 0.004). The prevalence of transfusion transmissible infections was significantly higher among male blood donors compared to female donors, among the age group of 25-32 years and 33-40 years compared to the age group of 18-24 years old, and among unemployed and private workers compared to students. CONCLUSION: A significant percentage of the blood donors harbor transfusion-transmissible infections.Stringent donor selection using standard methods is highly recommended to ensure the safety of blood for the recipient. Furthermore, efforts on motivating and creating awareness in the community are required to increase voluntary blood donors. KEYWORDS: Transfusion transmissible infections, prevalence, Trend, Ethiopia