Between November 2000 and the end of 2007, five outbreaks of foot and mouth disease (FMD) occurred in cattle in the area adjacent to the Kruger National Park (KNP) in the north-eastern corner of South Africa. To help understand the factors behind these outbreaks a qualitative risk assessment based on the World Organisation for Animal Health (OIE) assessment framework was adopted, using available data from published sources and various unpublished South African sources. Risk was assessed on the basis of the following factors: data on South African Territories (SAT) type infections of buffalo and impala in the KNP, permeability of the fence along the western boundary of the KNP, the potential for contact between livestock and wildlife susceptible to FMD in areas adjacent to the KNP, and the level of herd immunity in cattle generated by prophylactic vaccination. Scenario pathways for FMD occurrence outside the KNP are presented as a conceptual framework to qualitatively assess the risk of FMD outbreaks. Factors that are likely to have most influence on the risk were identified: fence permeability, vaccination coverage, or the efficiency of animal movement control measures. The method and results are provided as an approach that may be used as a basis to evaluate the risk of FMD outbreaks occurring in other wildlife/livestock interface areas of southern Africa.