BACKGROUND Accurate estimates of the risk of transfusion-transmitted infectious disease are essential for monitoring the safety of the blood supply and evaluating the potential effect of new screening tests. We estimated the risk of transmitting the human Immuno-deficiency virus (HIV), the human T-cell lymphotropic virus (HTLV), the hepatitis C virus (HCV), and the hepatitis B virus (HBV) from screened blood units donated during the window period following a recent, undetected infection. METHODS Using data on 586,507 persons who each donated blood more than once between 1991 and 1993 at five blood centers (for a total of 2,318,356 allogeneic blood donations), we calculated the incidence rates of seroconversion among those whose donations passed all the screening tests used. We adjusted these rates for the estimated duration of the infectious window period for each virus. We then estimated the further reductions in risk that would result from the use of new and more sensitive viral-antigen or nucleic acid screening tests. RESULTS Among donors whose units passed all screening tests, the risks of giving blood during an infectious window period were estimated as follows: for HIV, 1 in 493,000 (95 percent confidence interval, 202,000 to 2,778,000); for HTLV, 1 in 641,000 (256,000 to 2,000,000); for HCV, 1 in 103,000 (28,000 to 288,000); and for HBV, 1 in 63,000 (31,000 to 147,000). HBV and HCV accounted for 88 percent of the aggregate risk of 1 in 34,000. New screening tests that shorten the window periods for the four viruses should reduce the risks by 27 to 72 percent. CONCLUSIONS The risk of transmitting HIV, HTLV, HCV, or HBV infection by the transfusion of screened blood is very small, and new screening tests will reduce the risk even further.