With the name of High Priestess and Moon being used in this game, this means all of the Tarot cards name in Major Arcana section have all been used, save for The Devil. Also, High Priestess and Moon are the first two bosses chronologically to not have Type Number displayed in their profiles.
This is the first game in the series to have the colour of the players switched, resulting in P1 as Blue and P2 as Red, as opposed to the traditional P1 as Red and P2 as Blue. This probably because the character of Ryan wearing a Dark Blue suit, while Kate is wearing a Red dress.
This is the first game in the series that didn't feature G at all, either as Playable Character or Non-Playable Character.
This is the first game in the series to have "The" part in the title removed, leaving only House of the Dead.
The Powerpuff Girls buttercup, StarBeam Henry, House of the Dead Scarlet Dawn and 2022 Grand 22 Theatres Bismarck ND, Arcade