Alice Wright is an agent for the Department 42, a special government agency that deals with supernatural cases. The agency stored for safekeeping nine powerful amulets inside the Grimstone Mansion, a place protected by magic spells. After a fire destroys the building, the artifacts disappear and Alice is assigned to retrieve them.

Department 42: The Mystery of the Nine is third attempt by Frogwares in casual gaming. Like their previous efforts, it's a hybrid game mixing hidden object and adventure mechanics. This time the design is more traditional, with the gameplay moving between well-defined sections for the adventure and hidden object portions.

The game is divided in cases, where the objective is to find and retrieve one of the nine lost artifacts. The locations are presented as a series of mostly static screens, where the player has to search and click on all the objects listed at the bottom. Some of the retrieved items are stored inside the inventory, to be used later when solving puzzles. In the adventure sections, the list is replaced by the inventory, from where the stored objects can be dragged and dropped on parts of the scenery in a logical way.

Interactive portions of the scene shimmer to make them more obvious to the player. When clicking on these glimmering spots, they sometimes open a window with a close-up view of the scenery. Some puzzles take place on separate screens, where a mechanism has to be manipulated directly to fix or create some item necessary to solve the case. The bottom interface also has a map to move between locations, and a list of the remaining case objectives. The hint button shows the position of one of the required items, but takes some time to recharge after use.

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