| Achievement | How to unlock | Points
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| - Collect all items and unlock all secrets.
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| - Kill Mom's Heart nine times.
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| - Kill Mom's Heart 8 times.
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| - Make three deals with the devil in one run.
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| - Beat the Basement/Cellar without taking damage.
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| - Beat Hard mode as Lazarus without losing a life.
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| - Kill Mom's Heart ten times.
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| - Hold 55 or more pennies at one time.
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| - Beat all twenty Challenges.
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| - Beat the Depths/Necropolis without taking damage.
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| - Beat the Chest or Dark Room without taking damage.
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| - Beat the Womb for the first time.
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| - Kill Mom's Heart five times.
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| - Beat two levels in a row without picking up any hearts.
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| - Donate 500 coins to the Greed Machine.
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| - Kill Isaac with The Lost.
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| - Kill Isaac with Isaac.test
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| - Kill Mom's Heart eleven times.
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| - You are just like your father...
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| - Kill The Lamb with Keeper.
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| - Donate thousand coins in Greed Mode.
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| - Have four or more soul hearts at one time.
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| - Beat Greed Mode with Azazel.
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| - Collect two of either Roid Rage, The Virus, Growth Hormones, Experimental Treatment, or Speed Ball.
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| - Beat the Dark Room with Isaac.
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| - Have seven or more max red hearts at one time.
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| - Beat the Womb/Utero without taking damage.
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| - Beat everything in Hard Mode as every character.
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| - Collect all items and unlock all secrets and endings.
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| - The other side is calling...
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| - Beat two levels in a row without taking damage.
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| - Beat the Caves thirty times.
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| - Beat the Depths twenty times.
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- Something from the Future
| - Beat the Basement fourty times.
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| - Beat the Caves/Catacombs without taking damage.
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| - Kill The Lamb with Lilith.
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| - Uncover some lost remains...
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| - Kill Mom using the Bible.
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| - Finish the game's final secret.
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| - Kill Satan with The Lost.
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| - Beat Cathedral five times.
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| - Kill Mom's Heart 3 times.
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