This study investigates the evolution of SARS-CoV-2 during treatment of a chronic infection in an immunosuppressed individual. Whole-genome ultra-deep sequencing of 23 time points over 101 days and in vitro techniques were used to analyze mutations in the viral genome. The results show that chronic infection leads to viral evolution and reduced sensitivity to neutralizing antibodies. After two courses of remdesivir, there was little change in the viral population. However, after convalescent plasma therapy, there was a large, dynamic shift in the viral population, with the emergence of a dominant strain containing a substitution (D796H) in the S2 subunit and a deletion (ΔH69/ΔV70) in the S1 N-terminal domain of the spike protein. The emergence of this strain was associated with reduced susceptibility to neutralizing antibodies. In vitro, the spike double mutant bearing both ΔH69/ΔV70 and D796H conferred modestly decreased sensitivity to convalescent plasma, while maintaining infectivity levels similar to the wild-type virus. The spike substitution mutant D796H appeared to be the main contributor to the decreased susceptibility to neutralizing antibodies, but this mutation resulted in an infectivity defect. The spike deletion mutant ΔH69/ΔV70 had a twofold higher level of infectivity than wild-type SARS-CoV-2, possibly compensating for the reduced infectivity of the D796H mutation. These data reveal strong selection on SARS-CoV-2 during convalescent plasma therapy, which is associated with the emergence of viral variants that show evidence of reduced susceptibility to neutralizing antibodies in immunosuppressed individuals. The study also highlights the importance of infection control measures tailored to immunocompromised patients and cautions against the interpretation of guidelines for immunocompromised individuals. The findings suggest that convalescent plasma therapy may not be effective in immunocompromised patients and that further research is needed to understand the viral dynamics and evolution in response to different selection pressures in immunocompromised individuals.This study investigates the evolution of SARS-CoV-2 during treatment of a chronic infection in an immunosuppressed individual. Whole-genome ultra-deep sequencing of 23 time points over 101 days and in vitro techniques were used to analyze mutations in the viral genome. The results show that chronic infection leads to viral evolution and reduced sensitivity to neutralizing antibodies. After two courses of remdesivir, there was little change in the viral population. However, after convalescent plasma therapy, there was a large, dynamic shift in the viral population, with the emergence of a dominant strain containing a substitution (D796H) in the S2 subunit and a deletion (ΔH69/ΔV70) in the S1 N-terminal domain of the spike protein. The emergence of this strain was associated with reduced susceptibility to neutralizing antibodies. In vitro, the spike double mutant bearing both ΔH69/ΔV70 and D796H conferred modestly decreased sensitivity to convalescent plasma, while maintaining infectivity levels similar to the wild-type virus. The spike substitution mutant D796H appeared to be the main contributor to the decreased susceptibility to neutralizing antibodies, but this mutation resulted in an infectivity defect. The spike deletion mutant ΔH69/ΔV70 had a twofold higher level of infectivity than wild-type SARS-CoV-2, possibly compensating for the reduced infectivity of the D796H mutation. These data reveal strong selection on SARS-CoV-2 during convalescent plasma therapy, which is associated with the emergence of viral variants that show evidence of reduced susceptibility to neutralizing antibodies in immunosuppressed individuals. The study also highlights the importance of infection control measures tailored to immunocompromised patients and cautions against the interpretation of guidelines for immunocompromised individuals. The findings suggest that convalescent plasma therapy may not be effective in immunocompromised patients and that further research is needed to understand the viral dynamics and evolution in response to different selection pressures in immunocompromised individuals.