This study analyzes trends in the residual risk of transmission of HIV, HBV, and HCV through blood transfusion over eight three-year periods from 1992 to 2001 and compares, for HIV and HCV, estimates of the benefit provided by viral genomic screening (VGS) with the results observed since its implementation in France on July 1, 2001. Since residual risk is primarily linked to the window period, it was estimated by multiplying the incidence rate of each infection by the duration of the window periods. For the first seven periods, incidence rates were calculated using data from institutions participating in the work of the “Transfusion-Transmissible Agents” group of the French Society of Blood Transfusion, which collect more than 50% of donations, and for the last period, based on all donations collected in France. Over the 1999–2001 period, the residual risk prior to DGV was estimated at 1 in 1,400,000 for HIV, 1 in 760,000 for HCV, and 1 in 450,000 for HBV. With mini-pool DGV, the residual risk becomes nearly two times lower for HIV (1 in 5 million donations) and seven times lower for HCV (1 in 2.5 million donations). During the first year of DGV, the two seronegative donations infected with HIV-1 (1 detected by DGV and 1 undetected) are consistent with estimates of residual risk and the benefit associated with DGV. Regarding HCV, the estimated benefit was three donations per year, whereas only one case was found to be RNA-positive and antibody-negative between July 1, 2001, and June 30, 2002. Before the DGV, the overall residual risk (HIV, HBV, and HCV) decreased from 1 in 65,000 to 1 in 235,000 donations between 1992 and 2001. With the DGV, the overall residual risk is 1 in 350,000 donations, which is one-third lower than before the DGV. The results of the DGV confirm the validity of the risk estimates provided by the model and the limited benefit of the DGV due to the low residual risk at the time of its implementation.