Background Blood transfusion is an effective treatment for saving millions of lives even though transfusion- transmissible infections are the major problem. Therefore, the aim of this study was to assess the sero-prevalence and trend of transfusion-transmissible infections among blood donors. Methods A retrospective study was conducted form July 2014 to June 2018 at Bahir Dar district blood bank. Descriptive statistics was presented using percentages, medians and interquartile ranges. Logistic regression was used to explore risk factors associated with each transfusion transmissible infections. Result From a total of 35,435 blood donors 2130 (6.0%) of them had serological evidence for at least one infection and 50 (0.14%) of them were confirmed as having multiple infections. The overall sero-prevalence of HBV, HCV, HIV and syphilis was 230 (6.0%) with 3.9%, 0.6%, 0.5% and 1.2% respectively. From those who had co-infection majority of them 22 (44.0%) were attributed to HBV-Syphilis co-infection and 1 (2.0%) study participant was co-infected with HBV-HIV- Syphilis infection. There was an increment in the overall prevalence of transfusion-transmissible infection;183 in 2014/2015 to 624 in 2017/2018. The sero-prevalence of HBV show a significant increment tend with respect to year of donation. On the other hand HCV and HIV sero-prevalence show an increasing trend from 2014 and decrease in 2018. The sero-prevalence of syphilis was 67 (1.3%) in 2015 and duplicate in 2016, 138 (1.5) but subsequently decrease to 110 (1.1%) in 2017 and in 2018 it was 114 (1.0%). Conclusion and recommendations His finding showed growing evidence in the burden of transfusion-transmissible infection in blood donors despite which requires advanced and vigilance screening of donated blood prior to transfusion. More over there should be strategies for monitoring the implementation of post donation counseling for recruitment and retention of safe regular donors.