Background: Transfusion-transmissible infections (TTIs) are of significant public health concern, as they can be transmitted through blood transfusions. Monitoring the trends and prevalence of TTIs is crucial for ensuring the safety of the blood supply and implementing effective preventive measures. This study aimed to analyzed the trend in seroprevalence of TTIs, including HIV, hepatitis B (HBV), hepatitis C (HCV), and syphilis (TPHA), among blood donors in the Buea Regional Hospital (BRH) from 2019 to 2023. Materials and Methods: This retrospective study was conducted using data from the Buea Regional Hospital Blood Transfusion Service. The study population included all blood donors who donated blood from January 2019 to December 2023. Serological testing for TTIs was performed using standard diagnostic methods. The prevalence of each TTI was calculated for each year, and the trends were analyzed using statistical tests and expressed as frequency tables, Chi square, logistic regression. Significance was set at p=0.05. Results: A total of 11,256 donors were tested and 919 (8.12%) blood donors tested positive for at least one TTI agent during the study period. The overall positivity rates were 8.23%, 9.48%, 6.65%, 8.29%, and 8.24% for 2019, 2020, 2021, 2022, and 2023, respectively. The prevalence of individual TTIs showed significant variations, with TPHA being the most prevalent (2.96%), followed by HBV (2.58%), HCV (1.15%), and HIV (1.24%). Socio-demographic factors, such as gender, marital status, occupation, and age, were found to be significantly associated (p<0.001) with the odds of testing positive for a TTI. Conclusion: The trend in the prevalence of TTIs among blood donors in the Buea Health Area was characterized by fluctuations over the five-year period.