Due to the fact that they will be at full health a larger portion of the time than most characters, this item is also very powerful for Keeper and Tainted Keeper.
If the damage is lost with Tainted Isaac, he can pick up another item in the same room and then swap it back to refresh the effect. Holding onto pedestal generation like Mystery Gift will allow him to place an item inside a difficult boss room and regain the bonus damage after being hit.
Using XI - Strength when already at a maximum 12 hearts, but having taken damage (hence visually having full maximum health) will not reactivate the item.
Holy Mantle: This will block damage and keep Crown of Light active.
Rock Bottom: While the diamond tear effect will disappear when Isaac is hit, the damage up will not be reverted.
Despite the pickup quote being "The untainted gain power" Tainted characters will still get the boost
If Isaac picks up a Bone Heart while the crown is glowing blue and leaves the current room, the crown will continue to glow blue even though the damage boost is inactive due to the Bone Heart container being empty. Taking any damage won't make the crown turn gray until Isaac fills all of his Red Heart containers and leaves the current room to reset the effect.