Background and Methods: Seventy-six heart transplants in 73 patients were studied for the formation of lymphocytotoxic panel-reactive antibodies after transplantation. Treatment of patient serum with dithioerythritol was used to discriminate between antibodies of the immunoglobulin M and immunoglobulin G isotypes. Human leukocyte antigen specificities of immunoglobulin G panel reactive antibodies were determined by the pattern of reactivity with the cell panel used in the panel-reactive antibodies determinations. A total of 465 panel-reactive antibodies determinations were made during the first year after transplantation. Results: Mean panel-reactive antibodies values were highest during the first posttransplantation month. Positive dithioerythritol-treated panel-reactive antibodies values were rare after the first month after transplantation. Multivariable analysis indicated that previous pregnancy and positive cytomegalovirus serologic analysis predicted a higher dithioerythritol-treated panel-reactive antibodies within the first 3 months. No decrease in actuarial survival, increase in cumulative rejection episodes, or increase in the incidence of coronary artery disease at 1 year was seen in patients with a standard panel-reactive antibodies greater than 10% or among patients with dithioerythritol-treated panel-reactive antibodies greater than 0%. A significant and major increase in rejection-related death or retransplantation occurred among 11 patients in whom donor human leukocyte antigen specific antibodies of the immunoglobulin G isotype were detected during the first posttransplantation year (p = 0.02). Two of the 11 patients died of refractory rejection at 3 and 6 months after transplantation, whereas one patient underwent retransplantation for refractory rejection at 13 months and subsequently died. Conclusions: (1) Posttransplantation serial standard panel-reactive antibodies or dithioerythritol-treated panel-reactive antibodies are not predictive of rejection-related mortality unless the specificity is determined to be antidonor HLA; (2) routine dithioerythritol- treated panel-reactive antibodies studies are advisable during the first month after transplantation, and, if positive (>10%), antidonor human leukocyte antigen specificity should be determined; (3) detection of recipient immunoglobulin G anti-donor human leukocyte antigen antibodies after heart transplantation identifies a group at high risk for serious allograft rejection and should prompt more intensive rejection surveillance and consideration for additional immunotherapy.