Sixty-one infants and children, 12 years old or younger, who received an orthotopic cardiac allograft between November 1985 and December 1989 were analyzed for the incidence of rejection. Rejection was diagnosed non-invasively within the first 3 months and during the first year. Rejection episodes were diagnosed by signs and symptoms according to previously reported criteria. Multiple regression analysis with recipient age, donor age, donor-recipient weight ratio, number of HLA mismatches, sex of the recipient, sex-encoded minor tissue antigen incompatibility (H-Y: female recipients receiving male donor organ), graft ischemic time, lowest cyclosporine level during the first 2 postoperative weeks, and prophylactic use of OKT3 showed that H-Y was the only significant contributing factor for rejection at 3 months and 1 year (r = 0.308, p < 0.02; r = 0.308, p < 0.02; respectively). Patients were divided into two groups: group 1, 45 patients who were H-Y compatible (male and female recipients receiving female donor hearts); and group 2, 16 patients who were H-Y incompatible (female recipients with male hearts). Patients in group 2 had significantly more episodes of graft rejection than did patients in group 1 by 3 months and by 12 months after heart transplantation (3 months: 2.75 +/- 1.48 versus 1.67 +/- 1.41, p < 0.05; 1 year: 4.80 +/- 1.87 versus 2.59 +/- 1.93, p < 0.01; respectively). There were six grafts lost due to rejection in group 2 (6/15, 37.5%) and 7 grafts lost (7/45, 15.5%) in Group 1 (not significant). Heart transplantation with H-Y incompatibility resulted in a significantly greater incidence of rejection episodes.