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This paper analyzes vulnerability to climate change of the farming sector in the Nile Basin of Ethiopia across different agro-ecological zones. We construct composite vulnerability indices, which integrate both the bio-physical conditions of the farming regions and the socio-economic conditions of the farm households to investigate overall vulnerability as well as adaptive capacity, exposure and sensitivity. Concerning overall vulnerability, findings show that, among the four agro-ecological zones considered in this study, the humid lowlands and drought-prone highland areas of the Nile Basin of Ethiopia are the most vulnerable zones. Findings also show that local farming systems where enset is the dominant crop in moisture-sufficient highland areas have the highest adaptive capacity, while the humid lowland zone is the lowest in terms of adaptive capacity to climate change. Regarding exposure and sensitivity, the drought-prone highland areas are the most exposed and most sensitive to climate change. The moisture-sufficient highland areas tend to be the least exposed and sensitive zones, even though population density is highest and the precipitation amount is declining over time. Findings imply that climate change adaptation should be placed within the broader context of development strategy and rural poverty reduction.