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Objective: To assess the effect of coronavirus disease 2019 (COVID-19) infection on heart transplant recipients requiring immunotherapy. To investigate the effectiveness of vaccination in immunosuppressed heart transplant recipients during the initial years of the COVID-19 pandemic, and to examine the timing of COVID-19 infections in heart transplant recipients’ posttransplantation. Patients and Methods: International data on COVID-19 infection in immunosuppressed populations is limited. Heart transplant recipients requiring immunotherapy are at risk for increased complications with COVID-19 infection. The availability of vaccination and temporal trends in this population has not been well described. We report outcomes in immunosuppressed patients during the initial years of the COVID-19 pandemic from March 1, 2019, to October 31, 2021, at Mayo Clinic in Florida. Results: A total of 98 patients were reviewed, of which 49 were COVID-19–positive (CP), and 49 were negative (CN). The cohort was well matched, with a median age of 58 years (49–65 years) in both groups. Females consisted of 41% in the CP group and 18.4% in the CN group. Immunosuppression was not significantly different for CP or CN patients. The median time from transplant to CP was 384 days (237–677 days). The CN group’s median follow-up after transplant was 947 days (737–1191 days). The CP hospitalization rate was 24% with only 1 death. More CP patients were vaccinated than the CN group (92% vs 78%, P=.025). Conclusion: Our study sheds light on COVID-19’s effect on heart transplant recipients and vaccination in this population. Our findings suggest a potentially heightened infection risk within the first 1.5 years posttransplant, highlighting the need to optimize management strategies and vaccine efficacy in this vulnerable group.