Toxigenic Vibrio cholerae is the etiological agent of cholera, an acute dehydrating diarrhoea that occurs in epidemic form in many developing countries. Aquatic ecosystem is the major habitat of toxigenic V. cholerae, where it interacts with various abiotic and biotic factors to survive. To acknowledge the seasonal appearance, endemic nature and genetic deviation of V. cholerae it is essential to understand the interaction of V. cholerae with biotic and abiotic factors in aquatic ecosystem. This article summarizes the ecological interaction of toxigenic V. cholerae with different abiotic and biotic factors in aquatic ecosystem during the interepidemic period and their effect in clonal shift due to change of population structure. Suitable salinity, pH, nutrient content, temperature and the presence of aquatic macrophytes, phytoplanktons, zooplanktons, fish, mollusks and crustaceans present in the aquatic ecosystem favors the survival of toxigenic V. cholerae. Diversity, relatedness and ecological interaction of toxigenic vibrio population in different habitats can bring changes in genetic make up due to natural stresses. In aquatic ecosystem V. cholerae interact with ecofactors for its survival and fluctuation in population structure may cause the dynamics of the diseases.