Background: The purpose of this report is to determine the extent of difficulty following and self-reported compliance with prescribed activities at 1 year after heart transplantation, identify postoperative predictors of compliance at 1 year after transplantation, and compare difficulty following and compliance with the therapeutic regimen at 1 year versus 2 years after transplantation. Methods: Data were collected from a nonrandom sample of 120 adult patients 1 year after heart transplantation and 76 of 120 patients 2 years after transplantation. Patients were 83% male, mean age 54 years, 86% were married, 28% were employed, and 91% were in NYHA class I at 1 year after transplantation. Data were collected from the Assessment of Problems with the Heart Transplant Regimen, Quality of Life Index, Heart Transplant Symptom Checklist, Sickness Impact Profile, Heart Transplant Stressor Scale, Jalowiec Coping Scale, Social Support Index, Heart Transplant Intervention Scale, Rating Question Form, and chart review. Data were analyzed via frequencies, multiple regression, paired t-tests, and the Wilcoxon matched-pairs signed- ranks test. Results: At both 1 year and 2 years after transplantation, patients had almost no difficulty following the heart transplantation regimen and complied almost all of the time with taking medications, attending clinic, and completing scheduled tests. Patients complied less with following a diet, exercising, and taking their vital signs. Predictors of compliance at 1 year after heart transplantation differed by prescribed activity, explaining from 13% to 52% of variance (p ≤ 0.0001). Conclusions: These findings indicate the need to continue the study of heart transplant recipient compliance longitudinally for individual prescribed activities and provide evidence and direction for the development of interventions to enhance patient compliance.