The usual methods employed to reduce the risk of transfusion-associated cytomegalovirus (TA CMV) disease have been to transfuse blood or cellular blood components that are CMV antibody-negative or to administer deglycerolized frozen red cells. To determine if the reduction of white cells (WBCs) in blood by filtration will also eliminate TA CMV disease in a high-risk population, 48 surviving very low birth weight (less than 1250 g) neonatal infants born to CMV-seronegative mothers at three participating institutions in the Hartford, Connecticut area and receiving at least one CMV-seropositive blood transfusion were studied. The incidence of TA CMV disease in 26 neonatal patients who received blood prepared by a modified spin-cool-filter technique and in 22 neonatal patients who received blood filtered through a WBC-reduction filter was compared with the incidence of transfusion-associated disease in similar populations reported in other studies. The CMV antibody prevalence of the blood donor population was found to be 37 percent. At the time of discharge of the individual neonatal infants in the population studied, and/or 2 to 6 months later, 47 of the 48 who had undergone transfusion had CMV antibody-negative serologic tests and/or urine culture. The other infant transiently seroconverted because of passive transfer of the antibody. None of the 48 neonatal infants had clinical evidence of CMV infection. This study indicates that WBC reduction of donor blood can reduce and perhaps prevent TA CMV disease in high-risk neonatal patients.