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The prefecture of Serres has a long history that is connected with tempestuous centuries of battles. The excavated sites have brought to light ruins from ancient settlements and remnants of ravages, while some Byzantine monuments, such as the church of Agioi Theodoroi, Agioi Anargyroi and Agios Nikolaos have been rescued. The archaeological findings show that the area of Serres was one of the oldest areas in Macedonia.
The archaeological findings also showed that the area was inhabited since the Palaeolithic era. During the time of Alexander the Great, the area contributed significantly in the cultural campaign of the Macedonians, since King Phillip used the gold mines of Pagaio Mountain to create and develop a solid economy. From 357 B.C. to 168 B.C., Amphipolis was the centre of Macedonia. Other ancient cities in the area were Irakleia, Skotoussa, Vissaltia, Trilon, Vergi, Myrkinos, Gazoros, Zichni and Draviskos.
During the Turkish invasion, the Greek Revolution and the Macedonian Battle, important Greek patriots such as Emmanouel Pappas, Kapetan Mitrousis, Doukas Doukas and others, initiated an action of independence.
During World War 1, the area came under the authority of the German and Bulgarian occupation forces, while during World War 2 the battle of Rupel fortresses took place. These fortresses were never occupied but they surrendered after the capitulation of the country.