FMD is an acute, highly communicable and economically important disease of livestock and wild animals. This study was conducted on FMD’s livelihoods impact, trend analysis and benefit-cost ratio of vaccination in Borena zone, of Ethiopia. The study used participatory appraisal methods and secondary data sources. The study clearly showed that FMD had the greatest impact on the cattle-derived benefits and the trend of outbreaks frequency and severity has been increasing with timeline. Furthermore, through the timeline, FMD outbreaks frequency and severity was found to be significantly correlated to length of extended dry season. The benefit from FMD vaccination is found to be 9.1 times that the expenses of the vaccination indicating that the control of FMD in Borena zone by vaccination could be justified on economic grounds. Although it is not expected for a vaccination program to lead to a disease free status in herds in the region soon, decreased FMD incidences that would imply less stress on people’s lives, secure food sources and social harmony and also might increase national and international trade opportunities.