Foot and mouth disease (FMD) is an endemic transboundary disease in the Mekong region, and FMD records of reports to animal health authorities in Lao PDR between 2009 and 2011 were reviewed. FMD outbreaks occurred in 2 of 3 years in eight districts in three of the eight northern Lao PDR provinces, locations suggested as FMD ‘hotspots’. The relatively higher risk of recurrence of FMD in these districts was likely due to the presence of a dense large ruminant population, extensive animal trading including transboundary movements and ineffective animal movement controls. As an understanding of the epidemiology of FMD in these ‘hotspots’ may offer insights into improved FMD control in the region, a study of an outbreak of FMD occurring in early 2010 following failure to vaccinate was conducted in the endemic ‘hotspot’ area of Paek district in Xiengkhoung province where in early 2009, a major outbreak of FMD in the district had been prevented in two villages by vaccination. The 2010 outbreak included collection of tissue samples 1 week after the onset of FMD that confirmed infection with FMD virus serotype O (Myanmar topotype) in a population of 239 large ruminants, comprising 167 cattle and 72 buffalo. A survey by interview of 30 farmers conducted in July 2010 documented high morbidity in cattle and buffalo (>90%) and identified disease risk factors, including increased trading of animals at the end of the rice harvest, plus several failures of biosecurity. In late 2010 and early 2011, a total of 40 and 72 serum samples were collected from large ruminants prior to and post-FMD vaccination respectively and tested by LPB-ELISA. Antibodies were present in the pre-vaccination samples attributable to previous exposure to FMD virus and significantly rising post-vaccination titres indicated likely temporary protection against future FMDV infection. It was concluded that to provide sufficient control of FMD in this ‘hotspot’, regular vaccination, particularly prior to the peak risk period in December-February, plus improved farmer knowledge of disease transmission risk and biosecurity, is required. Although low rural education standards and language barriers because of multiple ethnic groups pose a challenge for the successful delivery of extension programmes in northern Lao PDR, training to improve disease recognition and reporting plus village-level biosecurity practices is considered important in FMD ‘hotspots’ if sustainable regional initiatives directed at FMD control are to be achieved.