Background Detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA is completed through reverse transcriptase-PCR (RT-PCR) from either oropharyngeal or nasopharyngeal swabs, critically important for diagnostics but also from an infection control lens. Recent studies have suggested that COVID-19 patients can demonstrate prolonged viral shedding with immunosuppression as a key risk factor. Case presentation We present a case of an immunocompromised patient with SARS-CoV-2 infection demonstrating prolonged infectious viral shedding for 189 days with virus cultivability and clinical relapse with an identical strain based on whole genome sequencing, requiring a multi-modal therapeutic approach. We correlated clinical parameters, PCR cycle thresholds and viral culture until eventual resolution. Conclusions We successfully demonstrate resolution of viral shedding, administration of COVID-19 vaccination and maintenance of viral clearance. This case highlights implications in the immunosuppressed patient towards infection prevention and control that should consider those with prolonged viral shedding and may require ancillary testing to fully elucidate viral activity. Furthermore, this case raises several stimulating questions around complex COVID-19 patients around the role of steroids, effect of antiviral therapies in absence of B-cells, role for vaccination and the requirement of a multi-modal approach to eventually have successful clearance of the virus.