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An epidemiological investigation on the fish disease Epizootic Ulcerative Syndrome (EUS) was conducted from January to December 2011 in the Zambezi River System (ZRS) of Sesheke District in the Western Province of Zambia. The study aimed at determining factors associated with outbreaks of EUS,infection rate and distribution of the disease.Active surveillance was conducted where a total of 4,800 fish were inspected in February, June and October for gross EUS-like lesions and disease confirmed using histopathology.Results of the study implicate several predisposing environmental factors;heavy rains preceded outbreaks resulting in excess flooding which caused water levels to rise 2m higher than normal; predominantly gleysol and arenosol soils of the ZRS resulted in low water pH(4.53-6.5)Other factors significantly(p<0.05) associated with EUS outbreaks were:low total alkalinity (45.13±SE 0.0418),water temperature (20.94±SE 0.2173),ambient temperature(25.85±SE 0.3058),month (June)and site(lagoons)of sampling.Infection rate was 3% (144) of the 4,800 fishes sampled.There is indication that EUS has affected fish in ZRS from Kazungula to Chavuma Districts of Zambia.