The incidence, causes, and impact of acute infection were analyzed among 814 consecutive patients from 24 institutions undergoing primary heart transplantation between January 1, 1990, and June 30, 1991, with mean follow- up of 8.2 months (range 0 to 18 months). Sixty-nine percent of the patients had no infections during the follow-up, whereas 31% of patients had one or more infection episodes. The cumulative incidence of infections per patient was 0.41 at 3 months, 0.55 at 6 months, and 0.62 at 12 months after transplantation. Bacterial and viral infections were most common (47% and 41% of infections), with fungi and protozoa accounting for 12%. Overall mortality per infection was 13%, but mortality with fungal infections was higher (36%, p < 0.0001). The most common organ infected was the lung, with a mortality of 23%. The probability of infection by 12 months was higher when OKT3 or antithymocyte globulin induction therapy was used (41% versus 35%, p = 0.01). The single most frequent infecting organism was cytomegalovirus, accounting for 26% of all infections. The probability of cytomegalovirus infection by 12 months was increased with a cytomegalovirus-positive donor and cytomegalovirus-negative recipient (27% versus 15% in all others, p < 0.0001) and with the use of OKT3 or antithymocyte globulin induction therapy (19% versus 12% without induction therapy, p = 0.07). Infection remains the leading cause of death after heart transplantation. The hazard function of likelihood of developing each type of infection at various times after transplantation, as well as response to therapy, are discussed.