Guidelines for stopping COVID-19 patient isolation are mainly symptom-based, with isolation for 10 to 20 days depending on their condition. Here, we describe three deeply immunocompromised patients, each with different clinical evolutions. Asymptomatic carriage, symptom resolution, or superinfection with a second SARS-CoV-2 strain were observed, all leading to prolonged infectious viral shedding several months. We followed the patients epidemiological, clinical, serological data, infectiousness using viral culture and viral mutations accumulated over time. Understanding underlying mechanisms and frequency of prolonged infectiousness is crucial to adapt current guidelines and strengthen the use of systematic PCR testing before stopping isolation in immunocompromised populations.