Hmm... good question.
With most such things, yeah-- you can just disable the .esp, load the game, make a new save, exit the game, enable the .esp and load the new save. But SI overwrites the Oblivion.esm when you first install it, so I'm not sure if that would work with it.
All you can do is try. If you think you might want to be able to go back to your most recent save, then when you load the game with the DLCShiveringIsles.esp disabled, make a new save, so that if it doesn't work, you've at least got your current one to go back to.
I'm not sure if it's pertinent in this particular situation, but the way to make sure that you have a truly clean save is to load the game the way you want it (for instance, with Shivering Isles disabled) go into a cell in which nothing respawns (a player house is best for that) then wait 73 hours so that all the rest of the game world has respawned, then make a save and play from that one.