The first 33 heart-lung transplant recipients in our series were studied for evidence of CMV infection. CMV infection was diagnosed by a change in the serologic status, viral culture, or histology of lung tissue. Of 18 patients who were preoperatively negative for CMV antibody, eight received organs from CMV antibody-positive donors. Five developed pneumonitis (fatal in three)l; one survived primary CMV of the GI tract. Those who recovered from CMV pneumonitis received IV ganciclovir with CMV hyperimmune globulin given prophylactically from the time of transplantation. Only three of ten antibody-negative patients receiving organs from antibody-negative donors developed primary CMV, characterized by only fever in two but associated with rejection, and repeated infection was fatal in a third. CMV reactivation/reinfection occurred in seven of 15 (47 percent) without clinical disease in all but one case. Following heart-lung transplantation, CMV is the cause of considerable mortality and morbidity. We recommend that CMV antibody-negative recipients should receive organs only from antibody-negative donors. If a donor/recipient mismatch occurs, hyperimmune globulin and ganciclovir may improve survival.