The study investigates the evolution of SARS-CoV-2 during chronic infection in an immunocompromised individual treated with convalescent plasma. Over 101 days, the viral population underwent significant changes, with little change after two courses of remdesivir. However, convalescent plasma therapy led to dynamic shifts, including the emergence of a dominant strain with a substitution (D796H) in the S2 subunit and a deletion (ΔH69/ΔV70) in the S1 N-terminal domain. This strain showed reduced sensitivity to neutralizing antibodies, particularly due to the D796H mutation, which also impaired infectivity. The ΔH69/ΔV70 deletion increased infectivity, possibly compensating for the reduced infectivity of D796H. The data highlight strong selection pressure on SARS-CoV-2 during convalescent plasma therapy, resulting in variants with reduced susceptibility to neutralizing antibodies in immunocompromised individuals.The study investigates the evolution of SARS-CoV-2 during chronic infection in an immunocompromised individual treated with convalescent plasma. Over 101 days, the viral population underwent significant changes, with little change after two courses of remdesivir. However, convalescent plasma therapy led to dynamic shifts, including the emergence of a dominant strain with a substitution (D796H) in the S2 subunit and a deletion (ΔH69/ΔV70) in the S1 N-terminal domain. This strain showed reduced sensitivity to neutralizing antibodies, particularly due to the D796H mutation, which also impaired infectivity. The ΔH69/ΔV70 deletion increased infectivity, possibly compensating for the reduced infectivity of D796H. The data highlight strong selection pressure on SARS-CoV-2 during convalescent plasma therapy, resulting in variants with reduced susceptibility to neutralizing antibodies in immunocompromised individuals.