The current standard of hand palpation may not be a sensitive method to detect rejection in heterotopic heart xenotransplants (HHTx). We sought to assess the use of echocardiography to detect rejection of pig heart xenografts. Four cynomolgus monkeys received HHTx from hDAF-transgenic pigs. Immunosuppression was cyclophosphamide induction, cyclosporine, steroids, sodium mycophenolate, alphaGal trisaccharide polymer, +/-soluble complement receptor type 1. Echocardiography was performed immediately after HHTx and three times a week postoperatively. Contractility on echo was scored as 1(none), 2(severely impaired), 3(moderate to severely impaired), 4(moderately impaired), 5(mild to moderately impaired), 6(mildly impaired), or 7(normal). Left ventricle wall thickness (LVWT) was measured in the anterior, inferior, posterior, lateral, and septal walls, the average was calculated. Impaired contractility or increase in LVWT were considered rejection and treated with steroids (solumedrol 15 mg/kg IV for 3-5 days). Palpation score (4-strong to 1-none) was recorded daily. Myocardial biopsies were obtained infrequently. At the time of first rejection, all four monkeys had an increase in LVWT and a decrease in contractility on echocardiography. Steroid treatment enhanced contractility in four monkeys and decreased LVWT in three monkeys. Palpation score remained at four of four during initial rejection episodes. Decrease in contractility and increase in LVWT on echocardiography appear to signify graft injury because steroid treatment results in improvement. Compared to palpation, echocardiography is more sensitive for assessing function of heterotopic pig heart xenografts. Echocardiography has, therefore, the potential to detect and treat early rejection episodes of heterotopic heart xenografts in nonhuman primates. This may help to achieve longer graft survival.