Abstract The oral polio vaccine (OPV) contains live-attenuated polioviruses that induce immunity by causing low virulence infections in vaccine recipients and their close contacts. Widespread immunization with OPV has reduced the annual global burden of paralytic poliomyelitis by a factor of ten thousand or more and has driven wild poliovirus (WPV) to the brink of eradication. However, in instances that have so far been rare, OPV can paralyze vaccine recipients and generate vaccine-derived polio outbreaks. To complete polio eradication, OPV use should eventually cease, but doing so will leave a growing population fully susceptible to infection. If poliovirus is reintroduced after OPV cessation, under what conditions will OPV vaccination be required to interrupt transmission? Can conditions exist where OPV and WPV reintroduction present similar risks of transmission? To answer these questions, we built a multiscale mathematical model of infection and transmission calibrated to data from clinical trials and field epidemiology studies. At the within-host level, the model describes the effects of vaccination and waning immunity on shedding and oral susceptibility to infection. At the between-host level, the model emulates the interaction of shedding and oral susceptibility with sanitation and person-to-person contact patterns to determine the transmission rate in communities. Our results show that inactivated polio vaccine is sufficient to prevent outbreaks in low transmission rate settings, and that OPV can be reintroduced and withdrawn as needed in moderate transmission rate settings. However, in high transmission rate settings, the conditions that support vaccine-derived outbreaks have only been rare because population immunity has been high. Absent population immunity, the Sabin strains from OPV will be nearly as capable of causing outbreaks as WPV. If post-cessation outbreak responses are followed by new vaccine-derived outbreaks, strategies to restore population immunity will be required to ensure the stability of polio eradication. Author Summary Oral polio vaccine (OPV) has played an essential role in the elimination of wild poliovirus (WPV). OPV contains attenuated yet transmissible viruses that can spread from person-to-person. When OPV transmission persists uninterrupted, vaccine-derived outbreaks occur. After OPV is no longer used in routine immunization, as with the cessation of type 2 OPV in 2016, population immunity will decline. A key question is how this affects the potential of OPV viruses to spread within and across communities. To address this, we examined the roles of immunity, sanitation, and social contact in limiting OPV transmission. Our results derive from an extensive review and synthesis of vaccine trial data and community epidemiological studies. Shedding, oral susceptibility to infection, and transmission data are analyzed to systematically explain and model observations of WPV and OPV circulation. We show that in high transmission rate settings, falling population immunity after OPV cessation will lead to conditions where OPV and WPV are similarly capable of causing outbreaks, and that this conclusion is compatible with the known safety of OPV prior to global cessation. Novel strategies will be required to ensure the stability of polio eradication for all time.