A cross sectional study was undertaken from November 2018 to April 2019 with the purpose of estimating the occurrence of Salmonella and to assess drug resistant profile of Salmonella isolated from economically fish species of Lake Tana. Multistage sampling technique was applied for selecting study districts, kebeles and individual fish. Systematic random sampling was used to sample individual fish and landing sites, while fish processors were selected purposively based on their willingness and experience of fishing activities. Tilapia, Leobobarbus and catfish were economically important fish groups in the Lake. Samples were taken from different parts of these three species. Samples from muscle (34.29 %) were found more Salmonella positive followed by gill (2.14%). The overall occurrence of Salmonella in the study area was 36.43%. Drug susceptibility test was done by disk diffusion method and interpreted based on Clinical Laboratory Standard Institute recommendations. Twenty five percent of Salmonella isolates (13 of 51) showed resistance at least for one drug. Ciprofloxacin (CIP-5μg) was found the highest (9.8%) followed by Ceftazidime (CAZ-30μg), 4.88% which salmonella developed resistant from the other drugs. Factors independently predict to salmonella occurrence were presence of contamination 1.1 (AOR= 1.06; 95%CI=1.04, 1.4), fish that was not iced after landing 2(AOR= 2.2; 95%CI=0.01, 5.41) and poor handling practice 2(AOR=1.8; 95%CI=0.001, 3.32). Isolation of Salmonella from fish may be associated with contamination of the harvesting areas, contamination of the harvesting, collecting and processing materials and equipments. In conclusion Salmonella is widely distributed in fish harvested from Lake Tana and hence appropriate control measures should be implemented to mitigate the problem. Key words: Associated risk factors,Drug résistance,Fish Species (catfish,labeobarbus,tilapia), Lake Tana, Salmonella