Solid-organ transplant (SOT) recipients are at a high risk of severe COVID-19, and are priority for vaccination. Here, we describe three cases of severe COVID-19 caused by SARS-CoV-2 B.1.1.7 lineage in vaccinated SOT recipients. Three SOT patients were hospitalized in the Policlinico Hospital of Bari (southern Italy) and underwent nasopharyngeal swabs for molecular detection of SARS-CoV-2 genes and spike protein mutations by real-time PCR. One sample was subjected to whole-genome sequencing. One patient was a heart transplant recipient and two were kidney transplant recipients. All were hospitalized with severe COVID-19 between March and May 2021. Two patients were fully vaccinated and one had received only one dose of the BNT162b2 mRNA vaccine. All the patients showed a high viral load at diagnosis, and molecular typing revealed the presence of B.1.1.7 lineage SARS-CoV-2. In all three cases, prolonged viral shedding was reported. The three cases pose concern about the role of the B.1.1.7 lineage in severe COVID-19 and about the efficacy of COVID-19 vaccination in immunocompromised patients. Protecting immunocompromised patients from COVID-19 is a challenge. SOT recipients show a suboptimal response to standard vaccination, and thus, an additive booster or a combined vaccination strategy with mRNA, protein/subunit, and vector-based vaccines may be necessary. This population should continue to practice strict COVID-19 precautions post-vaccination, until new strategies for protection are available.