That One Attack: Any ability that can cause confusion on multiple party members, since only up to three characters can be commanded per turn and the only item that can cure confusion from multiple characters is rare and hidden.
The Pirate Head and the Pirate Boss, due to being accompanied by two effectively-immortal Pirate mooks (as they're dismissed after acting and a fresh pair is summoned by the Head/Boss on his turn).
General Gohl loves to spam Confuse Powder on your entire front row, leaving who are likely your strongest attackers liable to wipe out the rest of your party. The battle becomes much easier if you only leave one character in the front row.
The Battleship. While it frequently wastes turns, its extremely high defense is a problem without defense-piercing IP abilities or defense-down debuffs and it hits extremely hard.
Amon, for his Spiritual Force of Chaos attack—hits every party member and has a chance to confuse. There's only three items that can prevent confusion at this point, with one of them being exclusive to Seena.
That One Level: Leydock's Mansion. You lose all but two of your party members (Wain and Dei) while fighting the enemies from the previous dungeon. Including Dark Elves, who can cast the aforementioned Destroy—and with only two party members on the receiving end instead of up to nine, there's a very good chance that it'll kill both characters together. Fortunately, Leydock himself is a solid Breather Boss.