A previous pilot study conducted on 12 bone marrow transplant recipients suggested that detection of cytomegalovirus (CMV) in lymphocytes was associated with a drop in lymphocyte counts and death due to CMV disease. To test the association between decreasing lymphocytes and CMV-related death, we undertook a retrospective study of 332 CMV-infected patients transplanted between 1987 and 1990. The patients were divided into three groups: I = 170 patients who survived their infection and were alive at the time of the study; II = 103 patients who died of causes other than CMV infection; and III = 59 patients who died of CMV disease. Lymphocyte counts were analyzed during a 24-day period, starting 10 days before the day of first positive CMV culture (day 0). Lymphocyte counts were significantly lower in Group III from day 0 through day +14 (p < .001 vs. group I; and p = .002 vs. group II). Multivariate statistical analysis was used to adjust for other differences between the groups that might influence lymphocyte numbers. Average lymphocyte counts in patients who died of CMV disease decreased by an average of 35% after day 0. The differences in lymphocyte counts remained independent of the effects of acute graft-vs.-host disease (GVHD), time since transplant, transplant type, and high-dose steroid treatment. In summary, these data suggest that in some patients a drop in lymphocyte counts is a consequence of CMV infection associated with fatal CMV disease. Whether this can be attributed to direct infection of lymphocytes, a defective immune response, or some other mechanism remains to be determined.