Background: Donated blood contaminated with S. Typhi can cause posttransfusion sepsis. This study aimed to determine the correlation between some risk factors of typhoid fever and seroprevalence of antibodies against S.Typhi among blood donors. Methodology: Following informed consent, socio-demographic and information on risk factors of typhoid infection was obtained using pre-structured questionnaires from 400 apparently healthy blood donors at the Tema General Hospital. Blood was also collected for serology and cultured for identification of pathogens by standard bacteriological method. Results: Blood culture did not reveal any S. Typhi isolate out of the tested 400 (348 males and 52 females) samples from apparently healthy blood donors. However, IgM and IgG antibody seroprevalence of 9.3% and 3.5% were detected. Age group of 17 -24 years was the highest risk group, persons with a history of typhoid infection, and sources of drinking water were major risk factors for typhoid infection. It was also observed that prevalence of IgM was highest among new donors (62.2%), but lower in donors with a history of 1 to 3 blood donations (32.4%) and least among regular donors (>3 donations (5.4%)). In addition, typhoid prevention awareness and typhoid knowledge (knowledge about typhoid transmission) among the donors were poor (4.3% and 5.9% respectively). Conclusions: This study has shown an overall seroprevalence of 9% and 3.5% for IgM and IgG antibodies respectively among blood donors in the Tema area in Ghana. We advocate for the mandatory screening of donor units intended for transfusion for S.Typhi. Furthermore, there is an urgent need for the health education of all persons in Ghana on preventive measures and the spread of S. Typhi.