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Wireless networks in an open environment are exposed to various large region threats, e.g., natural disasters and malicious attacks. Available works with regard to region failures generally adopt a kind of “deterministic” failure models, which failed to reflect some key features of a real region failure. In this paper, we provide a more general “probabilistic” region failure model to capture the key features of a region failure and apply it for the reliability assessment of wireless mesh networks. To facilitate such an assessment, we develop a grid-partition-based scheme to estimate the expected flow capacity degradation from a random region failure. We then establish a theoretical framework to determine a suitable grid partition such that a specified estimation error requirement is satisfied. The grid partition technique is also useful for identifying the vulnerable zones of a network, which can guide network designers to initiate proper network protection against such failures. This paper helps us understand the network reliability under a region failure and facilitates the design and maintenance of future highly survivable wireless networks.