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Environmental determinants causing unexpected disease rampant are seemed major challenges to be protective from inevitable hazards and to deal the future consequences in terms of human health loss. This paper explores the major environmental determinants stimulating disease prevalence in western hilly areas of Nepal. Cross-sectional analytical research design for household level primary data was treated with the binary logit regression model to identify the determinants of disease prevalence. Extreme winter temperature, decreasing winter rainfall, sporadic rain, drying spout and decreasing the tree species are the major environmental determinants; hand washing, proper management of solid waste from kitchen and habit of drinking boiled water are as household behavioral determinants; and adequate family members, higher education, use of pesticide to control the insects and use of clean cooking fuels are socioeconomic determinants encouraging disease prevalence. Plantation of large perennial and medicinal plants, proper management of warm clothes or heaters especially for old people and children having respiratory problems for extreme winter; management of water tank for long drought in winter and community awareness campaign for the protection of spout are urgent needs for the prevention of current disease prevalence. Ergo, the recommendations are made accordingly.