Aim: The most adverse effect of blood transfusion is the acquisition of transfusion-transmissible infections (TTIs), which poses a serious threat in developing countries. This study aims to identify the trends of transfusion-transmissible infections among blood donors.Materials and Methods: This study was a laboratory-based retrospective study conducted using blood donors’ records from January 2015 to December 2018, collected at the National Blood Transfusion Service, Guyana (NBTS). Analysis of data was performed using the Statistical Package for the Social Sciences (SPSS) version 22.0 software and the results were presented in tables and graphs. Chi-square and logistic regression were used to identify trends and influencing factors.Results: A total of 39,308 blood donors were included in this study, of whom 2,418 (6.2%) donors tested positive to at least one pathogen. Among those donors, 4.4% were coinfected with at least one of the sixteen dual infection combinations. The overall seroprevalence of HIV, HTLV, syphilis, HBV, HCV, Chagas, microfilaria, and malaria was 0.8%, 0.8%, 0.6%, 1.5%, 1.3%, 1.2%, 0.0%, and 0.0%, respectively. Trends of transfusion-transmissible infections showed an overall increase from the lowest prevalence, 5.1%, in 2015 to 7% in 2016, followed by decreases in 2017 (6.8%) and 2018 (5.8%).Conclusions: Even though 98.6% of the donor population are volunteers, this study has shown that a significant percentage of blood donors harbour transfusion-transmissible infections. Stringent screening and preventive measures are very important to ensure the safety of the transfusion recipient.