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The Ooze - Sega Genesis and Mega Drive
Not only is hard, the main character is very vulnerable and slow.
Phantasy Star II - Sega Genesis and Mega Drive
Immense labyrinths filled with dead-ends and random encounters! The fun!
The Adventures of Batman & Robin - Sega Genesis and Mega Drive
Technically impressive, but tough as nails.
Contra: Hard Corps - Sega Genesis and Mega Drive
At least the japanese version had a life bar!
Paulo Júnior's rating:

Chakan - Sega Genesis and Mega Drive
To top it off the difficulty, on its easy mode (called practice) the game ends early, thus is incomplete.
Eternal Champions - Sega Genesis and Mega Drive
Tough to get the hang of and the AI is really competent!
Paulo Júnior's rating:

Comix Zone - Sega Genesis and Mega Drive
Sega deemed it too short and so the devs had to make the game tougher to make up for it.
Kid Chameleon - Sega Genesis and Mega Drive
The game is already hard, but it also has 100+ levels and no saving feature.
Paulo Júnior's rating:

Streets of Rage 3 - Sega Genesis and Mega Drive
Only the western version, not Bare Knuckle III. The normal version in the west is the same as the hard mode in Japan, and the easy mode ends earlier, thus is incomplete.
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