The study was conducted in three regional states of Ethiopia: Amhara, Oromia, and Addis Ababa from August 2008 to April 2009 with the objectives of identifying the genetic diversity of serotypes and topotypes in Ethiopia, and determining the attack rate and associations of potential risk factors with foot-and-mouth disease (FMD) seropositivity. A total of 496 cattle were clinically and serologically examined for presence of specific lesions and nonstructural protein for FMD, respectively. Of which, 140 (28.2%) manifested clinical signs and lesions suggestive of FMD, and 219 (44.2%) were seropositive. From a total of 7,781 animals observed and recorded on a designed format in six districts, 1,409 (19.6%) were infected, and 15 (0.12%) died during outbreaks of FMD. Epidemiological investigations revealed that the morbidity rate of the disease was 21.1% in Akaki-kality sub-city, but the mortality rate was <2% in all districts. Furthermore, the mortality and case fatality rates were relatively higher, 1.6% and 8.9% in calves than the other age groups, respectively. From a total of 33 bovine epithelial tissue-cultured samples, 19 (57.6%) showed CPE for FMD virus, in which 16 samples had serotype O and EA-3 topotype, while three samples had found serotype A, Africa topotype, and G-VII strain. Various strains of FMD viruses were isolated in Ethiopia in this study, and therefore, further detailed studies on the evaluation of available vaccines and the development of a vaccine which contains cocktails of antigens of FMD virus strains in the country should be encouraged.