While untreated syphilis infection is characterized by spontaneous resolution of early lesions, a few organisms evade the host immune response and persist for many years. Macrophages are generally recognized as the effector cell responsible for bacterial clearance, and phagocytosis is enhanced by immune serum. This study examined the susceptibility of Treponema pallidum isolated at various stages of lesion resolution to opsonization and phagocytosis by macrophages in vitro. Findings suggest that the population of organisms remaining after the majority of bacteria have been cleared in vivo is resistant to phagocytosis. This may provide a mechanism for the persistence of T. pallidum in the face of an otherwise active immune response.