Human herpesviruses exhibit diverse pathogenic outcomes and the molecular reasons are not fully understood. Human herpesvirus 6B (HHV-6B) causes exanthema subitum and encephalitis, whereas the closely related HHV-6A is typically asymptomatic. Here, we show that cellular APOBEC3 enzymes restrict HHV-6A replication but not HHV-6B. HHV-6B expresses higher levels of the U28 protein, which binds multiple APOBEC3 proteins and promotes their relocalization and degradation. In contrast, HHV-6A fails to counteract APO- BEC3 activity and accumulates extensive mutations in both cell- and patient- derived viral genomes. Individual APOBEC3 gene ablation enhances HHV-6A replication and reduces the viral mutation burden. Together, our studies suggest that differential susceptibility to APOBEC3 restriction may help to shape the evolvability and clinical manifestations of HHV-6A and HHV-6B.