Foot and mouth disease (FMD) is endemic in the Lao People's Democratic Republic (PDR) and it causes economic loss to smallholder husbandry systems. An intervention programme based on a risk-based partial vaccination strategy was implemented in three provinces of Lao PDR (Champasak, Savannakhet and Xiangkhouang) to immunise domestic cattle and buffalo during 2016-2020. Two cross-sectional surveys were conducted in 2016/17 and 2020 to evaluate the impact of the vaccination programme on the prevalence of FMD virus exposure and clinical incidence of the disease. A total of 212 villages were visited during the two surveys, collecting 1609 household-level questionnaire results and 5931 blood samples of domestic cattle and buffalo. Blood samples were tested for the presence of antibodies to the non-structural proteins of FMD virus, and seroprevalence of 42.5 and 47.5% in 2016/17 and 2020, respectively were found. Multivariable regression analysis indicated that the efficacy of the FMD vaccination programme for reducing FMD virus circulation varied by province. In general, the incidence of clinical FMD increased toward the end of the 5-year intervention period, coinciding with a reduction of vaccine coverage in the last 2 years of the period. The findings suggest that the risk-based vaccination strategy achieved a marginally protective effect against the circulation of FMD virus with the possible limiting factors being operational constraints of public veterinary services, lack of farmers' compliance and unsustainable funding. We conclude that consistent resource availability and higher vaccination coverage is required to successfully control FMD with a risk-based vaccination strategy in Lao PDR.