This study investigates the evolution of SARS-CoV-2 in immunocompromised patients with prolonged infections, aiming to understand the pathways of viral evolution and the emergence of new pathogenic variants. Five patients with lymphoma or solid organ transplantation were enrolled, and their viral genomes were sequenced at multiple timepoints to monitor the accumulation of mutations. Four of the five patients had prolonged infections, while one experienced reinfection. The rates of mutation accumulation were higher in hospitalized patients with prolonged infections compared to the community background. The *spike* coding region accumulated significantly more unique mutations than other viral regions, and the mutation density was higher. Two patients treated with monoclonal antibodies (betbelovimab and sotrovimab) developed substitutions associated with resistance to these antibodies. Remdesivir-resistant mutations were not detected. The study highlights the potential for new viral variants to emerge in immunocompromised individuals, emphasizing the need for close monitoring of these patients to prevent the spread of drug-resistant strains.This study investigates the evolution of SARS-CoV-2 in immunocompromised patients with prolonged infections, aiming to understand the pathways of viral evolution and the emergence of new pathogenic variants. Five patients with lymphoma or solid organ transplantation were enrolled, and their viral genomes were sequenced at multiple timepoints to monitor the accumulation of mutations. Four of the five patients had prolonged infections, while one experienced reinfection. The rates of mutation accumulation were higher in hospitalized patients with prolonged infections compared to the community background. The *spike* coding region accumulated significantly more unique mutations than other viral regions, and the mutation density was higher. Two patients treated with monoclonal antibodies (betbelovimab and sotrovimab) developed substitutions associated with resistance to these antibodies. Remdesivir-resistant mutations were not detected. The study highlights the potential for new viral variants to emerge in immunocompromised individuals, emphasizing the need for close monitoring of these patients to prevent the spread of drug-resistant strains.