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Sequence can accommodate 2 to 12 players. In cases with more than three players, players must be evenly divided into two or three teams prior to the game's commencement. (Note that the game cannot be played with 5, 7, or 11 players.) In a two-team setup, players take turns positioning themselves opposite their opponents around the playing surface. For three teams, players from the same team must be situated at every third position around the playing surface.

The game board is placed on a flat surface, such as a floor or table, providing ample space for the game board, the draw deck, the discard pile(s), and marker chips. Jokers, if included, are removed from the deck since they are not utilized in the game.

To determine the starting player, all the cards are shuffled into a single deck. Each player selects a number of cards from the deck, flips them over, and reveals them. The player holding the lowest card becomes the dealer, and the cards are shuffled once more. Each player or team then selects a set of poker chips; all members of the same team use chips of the same color (blue and green chips are always used, while red chips are exclusively employed in three-player or three-team games).

The number of cards dealt to each player depends on the number of participants:

  • Two players: Seven cards each
  • Three or four players: Six cards each
  • Six players: Five cards each
  • Eight or nine players: Four cards each
  • Ten or twelve players: Three cards each

Every card appears twice on the game board, with Jacks not being present on the board but still crucial for game strategy.

The player to the left of the dealer initiates the game.

During their turn, a player selects a card from their hand and places a marker chip on the corresponding space of the game board (e.g., if an Ace of Diamonds is played from a player's hand, they place a chip on the Ace of Diamonds space on the board). Jacks possess unique abilities: Two-Eyed Jacks are wild cards, allowing players to place a chip on any open space on the board, while One-Eyed Jacks permit the player who played one to remove an opponent's chip from a space. Two-Eyed Jacks can be strategically used to complete a row or obstruct an opponent, while One-Eyed Jacks can neutralize an opponent's advantage. One-Eyed Jacks, however, cannot remove a marker chip that is already part of a completed sequence; once a sequence is achieved by a player or team, it remains intact.

Each card played is then placed face-up in a "Discard" pile. After completing their turn, the player draws a new card from the draw deck, and play proceeds to the player on the left.

A player is allowed to place chips on either of the appropriate card spaces as long as it is not already covered by a marker chip of any color.

If a player possesses a card for which there is no available space on the game board, the card is considered "dead" and can be discarded during that player's turn. Subsequently, the player draws a new card from the draw deck before continuing with normal gameplay.