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Water is a critical natural resource that sustains the productivity of many economic sectors, whether directly or indirectly. Climate change alongside rapid growth and development are a threat to water sustainability and regional productivity. In this paper, we develop an extension to the economic input-output model to assess the impact of water supply disruptions to regional economies. The model utilizes the inoperability variable, which measures the extent to which an infrastructure system or economic sector is unable to deliver its intended output. While the inoperability concept has been utilized in previous applications, this paper offers extensions that capture the time-varying nature of inoperability as the sectors recover from a disruptive event, such as drought. The model extension is capable of inserting inoperability adjustments within the drought timeline to capture time-varying likelihoods and severities, as well as the dependencies of various economic sectors on water. The model was applied to case studies of severe drought in two regions: (1) the state of Massachusetts (MA) and (2) the US National Capital Region (NCR). These regions were selected to contrast drought resilience between a mixed urban–rural region (MA) and a highly urban region (NCR). These regions also have comparable overall gross domestic productsmore »despite significant differences in the distribution and share of the economic sectors comprising each region. The results of the case studies indicate that in both regions, the utility and real estate sectors suffer the largest economic loss; nonetheless, results also identify region-specific sectors that incur significant losses. For the NCR, three sectors in the top 10 ranking of highest economic losses are government-related, whereas in the MA, four sectors in the top 10 are manufacturing sectors. Furthermore, the accommodation sector has also been included in the NCR case intuitively because of the high concentration of museums and famous landmarks. In contrast, the Wholesale Trade sector was among the sectors with the highest economic losses in the MA case study because of its large geographic size conducive for warehouses used as nodes for large-scale supply chain networks. Future modeling extensions could potentially include analysis of water demand and supply management strategies that can enhance regional resilience against droughts. Other regional case studies can also be pursued in future efforts to analyze various categories of drought severity beyond the case studies featured in this paper.« less