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The tenth entry of the Mega Man series.
In the year 20XX, an outbreak of a robotic-virus known as the "Roboenza" runs rampant across the globe. Roll becomes infected with the virus, and the situation becomes worse as time passes and a cure is not found. Several robots become berserk and attack the city. One day, Dr. Wily appears in Dr. Light's lab with his capsule damaged and asks for help. Mega Man saves Wily from crashing and Wily says that Roboenza-infected robots attacked his spaceship and stole the parts to the of a medicine-making machine he had been working on to cure the virus. Mega Man agrees to retrieve the stolen parts from the eight Robot Masters. Before he begins, Proto Man arrives to help Mega Man, believing the job to be too big for just one of them and the two join forces to acquire the cure. Meanwhile, Bass sets out on his own to challenge these new robots.
- DWN-073: Blade Man, weak to Commando Bomb, gives Triple Blade
- DWN-074: Pump Man, weak to Thunder Wool, gives Water Shield
- DWN-075: Commando Man, weak to Wheel Cutter, gives Commando Bomb
- DWN-076: Chill Man, weak to Solar Blaze, gives Chill Spike
- DWN-077: Sheep Man, weak to Rebound Striker, gives Thunder Wool
- DWN-078: Strike Man, weak to Triple Blade, gives the Rebound Striker
- DWN-079: Nitro Man, weak to Chill Spike, gives the Wheel Cutter
- DWN-080: Solar Man, weak to Water Shield, gives Solar Blaze
- Be the Ball: Strike Man.
- Bonus Boss: The Mega Man Killers. Not only that, but if you defeat them, Mega Man can use their weapons in the main game (sadly, Proto Man and Bass cannot).
- Call Back: The Sequential Boss of the first Wily level is a series of capsules containing the powers of various robot masters from 1-9; Elec Man, Wood Man, Gemini Man, Ring Man, Napalm Man, Flame Man, Slash Man, Frost Man, and Tornado Man.
- Ceiling Cling: Blade Man
- Chekhov's Gun: the prototype cure that Wily gave to Roll.
- Dual Boss/SpotTheImpostor: the Final Boss, where there are two Wily Capsules, one piloted by the real Wily and the other a decoy.
- Fire, Ice, Lightning: Solar Man, Chill Man, Sheep Man, respectively.
- Giant Enemy Crab: the second Fortress Boss.
- Gretzky Has the Ball: Strike Man's level; a baseball-themed robot master, with stage enemies that utilize soccer balls and footballs as well.
- Instant Plunder, Just Add Pirates: The Wily Machine of this game sports a pirate hat, for no other reason than Rule of Cool.
- Foreshadowing: A subtle bit of this happens in the reveal to Wily's being behind the actual plot (sort of): When making his world takeover announcement, while laughing, he suddenly coughs before stating the people wouldn't understand. Turns out Wily himself had fallen ill with presumably influenza, which Mega Man, Bass, and/or Proto Man discovering this after besting Wily aboard his space station.
- Last Day to Live: This is presumably the crux of Wily's latest plot, since when making his world domination speech he ends up coughing suddenly while meekly stating none will ever understand, which implies he was largely motivated in his recent world domination bid by his influenza. This might also explain his Pet the Dog moment in the ending where he created enough of the vaccine to cure all the robots prior to escaping the hospital.
- Overly Long Gag: Mega Man's upwards trip towards Wily's Space Station.
- Promoted to Playable: Proto Man is playable from the start this time, unlike Mega Man 9; this time, Bass, who was curiously absent in 9, is available via DLC. He plays virtually identical to how he did in Mega Man and Bass, only without the double-jump.
- Utility Weapon: Nitro Man's Wheel Cutter can be used to climb walls.