A three-dimensional semiconductor device includes first and second extended regions disposed on a substrate spaced apart from each other, a memory block disposed on the substrate between the first and second extended regions, and first and second main separation structures disposed on the substrate spaced apart from each other. The first extended region, the memory block and the second extended region are disposed between the first and second main separation structures. The memory block includes data storage regions and word lines. The word lines extend from the memory block and pass through the first and second extended regions. A distance between the first and second main separation structures located on both sides of the first extended region is greater than a distance between the first and second main separation structures located on both sides of the memory block.