Background: COVID-19 has an uncharacteristic course in immunodeficient patients, often contributing to diagnostic and therapeutic difficulties and the reactivation of latent infections. Objective: To describe the clinical course and therapeutic outcomes in immunocompromised patients with persistent COVID-19 who were found to have concurrent cytomegalovirus (CMV) reactivation, and to assess the potential impact of anti-CMV therapy on SARS-CoV-2 clearance. Material and methods: Four different cases of COVID-19 pneumonia and immune disorders were evaluated, and the intended effect was not achieved, despite multidirectional treatment aimed at SARS-CoV-2. This prompted further virological research to investigate the features of CMV reactivation. Results: Multidirectional treatment of COVID-19 in immunodeficient patients did not contribute to viral eradication. In all patients, high CMV viremia was observed with the use of ganciclovir/valganciclovir, which suppressed CMV replication and contributed to the elimination of SARS-CoV-2. Conclusions: This case series highlights the complex relationship between SARS-CoV-2 and CMV, emphasizing the need for a comprehensive virological evaluation of persistent COVID-19 cases. As the global medical landscape has grappled with the evolving challenges of the pandemic, incorporating such multifaceted clinical insights remains paramount.