Abstract Background Guidelines for stopping coronavirus disease 2019 patient isolation are mainly symptom-based, with isolation for 10 to 20 days depending on their condition. Methods In this study, we describe 3 deeply immunocompromised patients, each with different clinical evolutions. We observed (1) the patients’ epidemiological, clinical, and serological data, (2) infectiousness using viral culture, and (3) viral mutations accumulated over time. Results Asymptomatic carriage, symptom resolution, or superinfection with a second severe acute respiratory syndrome coronavirus 2 strain were observed, all leading to prolonged infectious viral shedding for several months. Conclusions Understanding underlying mechanisms and frequency of prolonged infectiousness is crucial to adapt current guidelines and strengthen the use of systematic polymerase chain reaction testing before stopping isolation in immunocompromised populations.