East Coast fever (ECF), one of the most serious tick-borne diseases in sub-Saharan and eastern Africa, was introduced to the island of Grande Comore in 2002 through zebu import from Tanzania, resulting in at least a 10% loss of livestock. A participatory epidemiology initiative was launched in 2015 to gain a better understanding of ECF epidemiology. Thirty-six villages were investigated involving 36 focus group sessions and 120 individual questionnaires. Farmers' knowledge of ECF and of priority diseases affecting the country was assessed, and the impacts of ECF and other major diseases were compared by a scoring method. The results showed that 69.4% (95% CI [51.3, 87.5%]) of the farmers had good to very good knowledge of ECF. The most important cattle diseases on Grande Comore were considered to be East Coast fever, heartwater, babesiosis, and cutaneous diseases. About 58% of the farmers (95% CI [49.2, 66.8%]) use curative treatments when cattle were sick. Between January and September 2015, the ECF incidence was estimated at 18.5% (95% CI [15.5, 21.4%]), and 87.5% (95% CI [72.7, 100%]) of the cattle infected by ECF died. The ECF incidence estimated in our study was found to be less when compared to that observed in Tanzania even though the climatic conditions in the Union of the Comoros are suitable for the biological vector of ECF, the tick species Rhipicephalus appendiculatus. Access to chemical treatment and its effectiveness against ECF, as well as controlling borders and organizing quarantine, are discussed.