Introduction A number of parenteral infections in third-world countries are caused by blood transfusions. Our objective was to determine the prevalence of and factors associated with infected blood obtained by the Honduran Red Cross through blood donations, to ensure the safety of the donated blood. Materials and methods This study used a cross-sectional analytical design based on the secondary analysis of data. Information on blood donors from San Pedro Sula, Honduras, between 2014 and 2016 were obtained from the database of the Honduran Red Cross. Data analysis was performed in two phases. The first phase described the variables, with the values presented as frequencies and percentages for categorical variables. The second phase involved a statistical analysis using generalized linear models. Results The proportions of donors who tested positive for syphilis, core hepatitis, hepatitis B, human T-cell lymphotropic virus, human immunodeficiency virus, and hepatitis C infections were 45% (n = 447), 35% (348), 11% (105), 10% (97), 6% (59), and 3% (24), respectively. The results of multivariate analysis demonstrated that the number of women positive for HIV infection was lower than that of men (p = 0.006). Older participants were more likely to be positive for core hepatitis (p = 0.029) and syphilis (p<0.001) infection but less likely to be positive for hepatitis B (p<0.001), hepatitis C (p = 0.027), human immunodeficiency virus (p<0.001), and human T-cell lymphotropic virus (p<0.001) infection compared to younger participants. Replacement donors had an increased likelihood of positivity for core hepatitis (p = 0.003) infections but a decreased likelihood of positivity for human T-cell lymphotropic virus infection (p = 0.001). Discussion The high prevalence of infectious diseases in Honduras warrants the need for monitoring donated blood to prevent infected blood from being provided for transfusions. Furthermore, education efforts through the creation of prevention programs are necessary to educate the Honduran population, especially younger individuals, about transfusion-transmissible infections.