To better understand the phenomenon of acute rejection in the current era of heart transplantation, complete rejection data (918 rejection episodes) from 25 institutions were analyzed for all 911 patients undergoing primary heart transplantation between January 1, 1990, and July 1, 1991. During a mean follow-up of 8.1 months (maximum, 18 months), 54% of the patients had one or more rejection episodes. The mean cumulative number of rejection episodes per patient was 0.8 at 3 months, 1.10 at 6 months, and 1.3 at 12 months after transplantation. By univariate analysis, female donor hearts (irrespective of recipient sex) (p < 0.01) and the use of induction therapy (p < 0.01) were associated with greater cumulative rejection frequency. By multivariate analysis, younger donor age and female donor gender were risk factors for earlier rejection. Solution of the multivariate equation predicted an 85% probability of rejection at 1 month for a 5-year-old female with a female donor and 50% for a 50-year-old man with a male donor. Inferences: (1) In the current era, over 40% of patients appear to be free of rejection during the first year after transplantation. (2) Younger recipient age and female donors are associated with earlier onset of allograft rejection, but the precise immunologic basis for these observations remains unknown. (3) In this experience, induction therapy did not delay the onset of first rejection nor did it reduce the cumulative number of rejection episodes. Further studies are indicated to examine the need for induction therapy.