Data on the safety and efficacy of SARS-CoV-2 vaccines in immunocompromised populations are sparse. We conducted a prospective study of 77 heart transplant (HT) recipients vaccinated with two doses of BNT162b2 vaccine and monitored for adverse events following both doses, the receptor-binding domain (RBD) IgG response, and neutralizing antibodies. BNT162b2 vaccination was associated with a low rate of adverse events, characterized mostly by pain at the injection site. By a mean 41 days post second dose there were no clinical episodes of rejection, as suggested by a troponin leak or allograft dysfunction. At a mean 21 days following the second dose, IgG anti-RBD antibodies were detectable in 14 (18%) HT recipients. Immune sera neutralized SARS-CoV-2 pseudo-virus in 8 (57%) of those with IgG anti-RBD antibodies. Immunosuppressive regimen containing mycophenolic acid was associated with lower odds of an antibody response (OR = 0.12, p = 0.042). Whether a longer time-frame for observation of an antibody response is required after vaccination in immunosuppressed individuals remains unknown.