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Debub shares its western border with the region of Gash-Barka, its northern flank with Maekel (central), and its eastern boundary with the Northern Red Sea Region. It is the largest region in the country by population.

This region has an area of around 8,000 square kilometers, and its capital is Mendefera (Adi Ugri). Other towns in Debub include Adi Keyh, Adi Quala, Dekemhare, Debarwa and Senafe. The archeological sites of Metera and Qohaito are also located here. The highest point in this region, and in Eritrea, is Mount Soira (3018 meters), situated east of Senafe.