From the early 1900s the Panionian Games were, together with the Panhellenic Games, the chief meeting points of Greek sports associations from Greece, Smyrna, Cyprus, Constantinople, Alexandria, Samos and other islands of the Aegean. The communication among associations and the common competitive activity constituted one of the fields where Greek irredentism became manifest and was kindled. Often the games were an opportunity for pro-union manifestations. In certain cases the Panionian Games were organized under the auspices of the SEAGS and the COG. That happened for the first time in 1906 and those games were a test for the formation of the Greek Olympic team for the Interim Olympic Games.
An important turning point in the history of the institution was the organization of 1899, as well as that of 1904. In 1899 the recently founded Panionian Gymnastic Association of Smyrna (which originated from the reunion of the Orpheus and the Gymnasium) undertook the organization of the games and published their regulations. The regulations ratified the English measuring system (yard, mile) something which was in force until the organization of 1903. However, in 1904 the regulations of the Panionian Games were harmonized with the international sports system for measuring the distances in the various contests, which had been adopted by Greece as well. In 1904 it was the first time that associations from Greece took part in the Games. The Panionian Games of 1907 were marked by remarkable entries and performances, since many new panhellenic records were set. 17 associations from Smyrna, Constantinople, Athens and Mytilene participated in the organization of 1909, perhaps the best in the history of the institution.
On the other hand, from 1910 onwards the Panionian Games were cancelled several times, due to the repeated wars and the tension in the Greek-Turkish relations. More precisely, the games between 1910 and 1914 were cancelled. In 1915 they were organized unofficially as local association games of the Panionian Gymnastic Association of Smyrna and in the two following years (1916-1917) they were cancelled. The games held in 1918 were of local range as well. The end of the war and the presence of the Greek army and administration in the region of Smyrna led to the panegyrical announcement of the Panionian Games of 1919. Nevertheless, these games were never held, not were those of the following year (1920) which were named Eleftheria, after the decision of the governor of Smyrna Aristidis Stergiadis. On the contrary, the organization of the Panionian Games of 1921 was allowed and it was the last to be held in Smyrna. After that came the collapse of the front in Asia Minor, the destruction of Smyrna, the refugees and the reestablishment of the Panionian in 1923 in Athens this time. During the following years the Panionian Games were organized in Athens, but they never regained the prestige, the range and the significance of the past.