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In the game of Harry Potter and the Half-Blood Prince, players return to Hogwarts to help Harry survive a fraught sixth year. They also have a chance to engage in exciting wizard duels, mix and brew magical ingredients in Potions class and take to the air to lead the Gryffindor Quidditch team to victory. Players even get sidetracked by Ron's romantic entanglements as they journey towards a dramatic climax and discover the identity of the Half-Blood Prince. The game itself is confirmed as a free roaming environment with indepth potions making, dueling and the fantastic sport of Quidditch.

The game will utilise the Wii Remote features as it did in the Harry Potter and the Order of the Phoenix video game. But unlike the previous game, players can now also use the motion sensing and vibration features to brew potions. Potion brewing involves following a complex recipe one step at a time. The steps include picking up vials of liquid, shaking them (by shaking the Wii Remote) until they froth, and tipping the Wii Remote to pour it into the mixture, being very careful not to pour in too much. Another possible step is stirring the mixture with the Wii Remote until it changes colour. If it starts vibrating, that is the sign to move away before it blows up.

Harry Potter can duel against Draco Malfoy in a Duelling Room with a long platform, similar to the one seen in the second film, but wider to allow dodging of spells. Moving in order to dodge is done with the Nunchuk joystick, while casting spells is done with Wii Remote and Nunchuk gestures. Combat spells currently implemented include a shield spell (likely "Protego") cast by crossing the Wii Remote and Nunchuk, a standard attack spell by striking downwards with the Wii Remote, a charged version by holding the Wii Remote up for longer first, and a more powerful attack spell by swinging the Wii Remote and Nunchuck to the left.