Antibodies have exquisite specificity to differentiate foreign antigens that mimic “self”, but it remains unclear how such specificity is acquired. We generated B-cells displaying an antibody that cross-reacts with two related protein antigens expressed on self versus foreign cells. B-cell anergy was imposed by self-antigen but reversed upon challenge with high-density foreign antigen, leading to germinal center recruitment and antibody gene hypermutation. Single cell analysis revealed rapid selection for mutations that decrease self-affinity and slower selection for epistatic mutations that specifically increase foreign-affinity. Strikingly, resolution of antigenic mimicry drove the optimal affinity maturation trajectory, highlighting the value of retaining self-reactive clones as substrates for protective antibody responses.