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Alien Syndrome is a top down shooter inspired by Sega's original Alien Syndrome action game. The games story takes place thousands of years in the future; by this point in time mankind has explored many parts of the galaxy and established numerous colonies. One such colony, Seti-Alpha 5 (SAT5), has ceased communications for some reason and it is your job to head to SAT5 and investigate what went wrong. Upon arrival, you encounter the alien syndrome, a force which can mutate man and machine into deadly aliens. These events take place roughly 100 years after those in the original Alien Syndrome.

When you begin the game you can select one of several characters as well as choose a character specialty (such as demolitions expert, firebug, seal, tank, and sharpshooter). The specialty you select will determine your initial character stats; as you play through the game you earn levels which provide you points to allocate towards improving your stats. The character stats help determine your characters accuracy in ranged or close attacks, speed, healing power, resistance to fire/radiation, armor strength, and so on.

Similar to the original game, the action is viewed top down. You'll need to explore the numerous corridors and rooms found on SAT5 and eliminate the numerous alien invaders found there. Mission objectives are often provided to you which need to be completed. Additional weapons, ammo, and other useful items can be found throughout the levels. Your character has a limited amount of energy, and if all energy is lost then you will need to begin again at the last checkpoint crossed.