The Crusades of the Middle Ages brought many challenges to relations between Roman Catholicism and Eastern Christianity in general. Major problems arose during the First Crusade with the creation of Latin Patriarchate of Jerusalem in 1099 and the attempts of its Latin clergy to suppress Orthodoxy in the Holy Land. At the same time, a new Latin Patriarchate of Antioch was created in 1100 and its existence was marked by the attempts of Latin clergy to suppress Orthodoxy in Syria. The later events of the Second Crusade and Third Crusade only worsened the situation.
The point of no-return was reached during the Fourth Crusade and the Sack of Constantinople (1204). Religious policy of Crusaders and Roman Catholic Church resulted in systematic suppression of Eastern Orthodox Church by take over of churches and monasteries, expulsion or persecution of Orthodox bishops, priests and monks after the creation of Latin Patriarchate of Constantinople and the forceful establishment of Catholic hierarchy throughout the Byzantine lands. Byzantine rule in Constantinople was restored in 1261 but various regions of Greece remained under local Latin rulers who continued to oppress Orthodox Christians until Turkish invasion in the 15th century.
During the 16th century, under the influence of the Catholic Counter-Reformation, rising pressures towards Orthodox Christians in White Ruthenia and other Eastern parts of Polish-Lithuanian Commonwealth led to the enforcement of the Union of Brest in 1595-96. Until that time, most Belarusians and Ukrainians who lived under the rule of Polish-Lithuanian Commonwealth were Orthodox Christians. Pressed by the state authorities, their hierarchs gathered in synod in the city of Brest and composed 33 articles of Union, which were accepted by the Roman Catholic Church.
At first, the Union appeared to be successful, but soon it lost much of its initial support, mainly due to its forceful implementation on the Orthodox parishes and subsequent persecution of all who did not want to accept the Union. Enforcement of the Union stirred several massive uprisings, particularly the Khmelnytskyi Uprising, of the Zaporozhian Cossacks and together alliance of Ukrainian Catholics and Belarussian-Ukrainian Orthodox because of which the Commonwealth lost Left-bank Ukraine.
In 1656, Greek Orthodox Patriarch of Antioch Macarios III Zaim lamented over the atrocities committed by the Polish Catholics against followers of Eastern Orthodoxy in various parts of Ukraine. Macarios was quoted as stating that seventeen or eighteen thousand followers of Eastern Orthodoxy were killed under hands of the Catholics, and that he desired Ottoman sovereignty over Catholic subjugation, stating: