Upon activation all pickups in the room (bombs, coins, hearts, keys, pills, tarot cards, trinkets, and chests) will randomly change into another pickup item, even undetonated troll bombs. The D20 can even help in combat as it will turn War's troll bombs into many pick-ups.
- Any item able to spawn a sufficient amount of pickups to transform, such as Pageant Boy or the IV Bag.
- The Habit can be used to abuse the Blood Donation Machine inside Arcade rooms along with the D20 to re-roll large amounts of coins and other potentially unwanted items. With a sufficient number of pickups on the screen enough hearts should be created to make up any lost health, and pickups re-rolled into chests can dramatically increase the number of available pickups to re-roll.
- The D20 is also effective if used quickly with the bombs from the Anarchist's Cookbook or The Tower, as they are also changed into other pickups.
- There is a hard limit of pickups that the D20 will re-roll in a single use (around 30).
- If D20 is used right after a coin is collected, the coin (with disappearing animation) will be also rerolled, so you can get both.
- Unlike the D6, the D20 cannot re-roll pickups that are for sale at the shop unless they have already been purchased without being picked up.
- The D20 is sometimes able to re-roll the remains of opened Chests, though only if any Collectable Items inside have been removed. This effect will not always work for unknown reasons.
- It may be a reference to Dungeons & Dragons, a popular tabletop role-playing game which uses a 20-sided die.