Food-and-mouth disease (FMD) is endemic in Cambodia. The control program for FMD has relied on vaccination, with poor vaccination uptake by smallholder farmers an increasing concern. A study to improve the understanding of farmer knowledge, attitudes and practices of FMD and FMD vaccination was conducted in two Cambodian provinces. The aim was to identify opportunities to improve the disease control programs provided by both the government and private sectors. The survey comprised 300 smallholder farmers using a one-on-one interview technique. Results identified that over two-thirds of the respondent farmers had not vaccinated their cattle over two years. Of those who did, most cattle were vaccinated either once a year or once every three years. A booster had never been administered. FMD outbreaks occurred every year during the study period, with a morbidity rate of over 30%. Isolation of first infected cattle from the household herd was not practiced, with treatment identified as the first preference intervention. Farmers often assisted other farmers to restrain and treat infected cattle both before (57%) and after (43%) their own cattle were infected. This indicated that most farmers did not practice basic biosecurity measures and chose to report FMD outbreaks to the village animal health workers (VAHW), friends, neighbors, and relatives in preference to government officials. It was concluded that poor knowledge of disease transmission and biosecurity, with low FMD vaccination coverage and a focus on treatment, contribute to regular FMD outbreaks in these communities. Improvement of FMD control requires the cooperation of villagers, VAHWs, and village leaders in disease reporting, with either improved funding of government vaccination services or private FMD vaccination service. Training programs for farmers on disease transmission, and the importance of biosecurity and vaccination, including information on the cost-benefits of treatment versus full fee bi-annual FMD vaccination, are required.