Evaluation and monitoring the prevalence of transfusion-transmissible viral infections in blood donors is a valuable index of donor selection and blood safety. This study analyzed the trends of blood-borne infections among Iranian blood donations during 4 years. Viral screening results of 6,499,851 allogeneic donations from 2004 through 2007 were analyzed. All donations were screened for hepatitis B virus (HBV), hepatitis C virus (HCV), human immunodeficiency virus (HIV), and syphilis. The prevalence of HBV, HCV, and HIV infections per 100,000 donations and 95% confidence interval was calculated. The p value was estimated by chi-square test. The prevalences of HBV, HCV, and HIV decreased during the 4-year study from 2004 through 2007. The overall prevalence was 0.56% for HBV, 0.004% for HIV, and 0.13% for HCV. There was a significant and impressive decrease in hepatitis B surface antigen prevalence from 0.73% in 2004 to 0.41% in 2007. The prevalence of HIV appeared to have decreased from 0.005% in 2004 to 0.004% in 2007 although the decrease was not significant. HCV prevalence showed a slight decline in blood donations from 0.14% in 2005 to 0.12% in 2007. The trends of transfusion-transmitted infection prevalence in Iranian blood donations suggest that most of the safety measures employed in recent years in Iran have been effective.