Cain starts with the Lucky Foot, medium health, and high damage output. Cain's strength lies in his versatility, his relatively balanced attributes make him well-suited to a variety of play styles.
The easiest way to unlock Cain is to use the Slot Machine until it explodes and provides A Dollar, which will instantly unlock him upon pick-up. The 2 Of Diamonds Suit Card is also useful, since it doubles the player's current Coins. Another strategy is to use the Blood Donation Machine while playing as Maggy.
- Cain is an excellent character to start with if you want to assemble the Pill Popper combo (Mom's Bottle of Pills + 9 Volt, The Battery, or the Habit), as his Lucky Foot guarantees you only positive or neutral pill effects. Mom's Coin Purse is useful for the same reason. D20 can prove immensely useful in the Arcade or coin-knocking enemies as large amounts of pickups are spawned in a single room and rerolling D20 has quite a chance to spawn a pill.
- Cain is tied with Eve for highest starting speed. Use this to your advantage; Cain is a capable hit-and-run character. Zip into combat and zip out again; your low range won't even matter if you can dodge well (and if you can't, Cain's a good character to practice with; he's more forgiving of mistakes than Judas).
- Cain's hit-and-run playstyle allows him to make use of burst-damage tears, i.e. Mutant Spider.
- Always go for the shell game in the Arcade first; the Lucky Foot means that you have a higher chance of winning the shell game than the slots.
- While in an Arcade, try to use the Blood Donation Machine to convert any leftover hearts you win into coins. Don't be afraid to donate health until you're down to one or two hearts, since the donation machine will often explode and leave the Blood Bag as a reward. Doing this for a few levels significantly raises Cain's health and therefore especially helps making deals with the devil more feasible.
- Soul Hearts can offset Cain's lack of durability; as always, keep an eye out for X Marks the Spot rocks and blow them up.
- As Red Chests have a chance of dropping 2 pills, Curse Rooms have higher chance of paying off.
- If you find a Fortune Telling Machine, use it as much as possible, as lucky foot gives 100% chance of item drops from it.
- PHD (redundant with your starting item, although it does identify pills before you use them, along with the healing)