Confessionalism has held a major space in political and religious debates in the Arab world since the early 1980s, following the Islamic revolution in Iran. With the evolution of political events, the space devoted to discussion of confessionalism grew to include historical invocations in an attempt to assert that confessionalism in the Arab Levant has a long past. This is fundamentally linked to the relationship between the Ottoman state that dominated the Levant and the Safavid state that ruled Iran. This paper looks at the effect of confessional difference on the relationship between the Safavid state and the Ottoman state. It focuses on the behavior of these two states towards each other and the way in which their relationship developed. Was their animosity or hostility the result of confessional difference, or were there other factors that interacted, such as the nationalist dimension and geographic competition?