This study investigates the evolution of SARS-CoV-2 in immunocompromised patients with prolonged infections. Five patients with extended SARS-CoV-2 infections were analyzed, revealing higher mutation rates compared to the general population. The spike protein region showed the highest mutation density, with mutations associated with monoclonal antibody resistance becoming dominant in two patients. Remdesivir-resistant mutations were not detected, suggesting that this drug may not be effective against these variants. The study highlights the potential for new viral variants to emerge in immunocompromised individuals due to prolonged viral persistence and selective pressures. The findings suggest that immunocompromised patients may serve as a source of new variants, emphasizing the need for close monitoring. The study also shows that viral evolution rates in these patients are significantly higher than in the general population, with some patients showing up to three times the mutation rate. The research underscores the importance of understanding viral evolution in immunocompromised individuals to improve treatment strategies and pandemic preparedness. The study provides insights into the mechanisms of viral evolution and the development of drug resistance in these patients.This study investigates the evolution of SARS-CoV-2 in immunocompromised patients with prolonged infections. Five patients with extended SARS-CoV-2 infections were analyzed, revealing higher mutation rates compared to the general population. The spike protein region showed the highest mutation density, with mutations associated with monoclonal antibody resistance becoming dominant in two patients. Remdesivir-resistant mutations were not detected, suggesting that this drug may not be effective against these variants. The study highlights the potential for new viral variants to emerge in immunocompromised individuals due to prolonged viral persistence and selective pressures. The findings suggest that immunocompromised patients may serve as a source of new variants, emphasizing the need for close monitoring. The study also shows that viral evolution rates in these patients are significantly higher than in the general population, with some patients showing up to three times the mutation rate. The research underscores the importance of understanding viral evolution in immunocompromised individuals to improve treatment strategies and pandemic preparedness. The study provides insights into the mechanisms of viral evolution and the development of drug resistance in these patients.