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Nemesis is the first entry in the long-running Gradius series on the Game Boy. Its side-scrolling shoot'em up gameplay follows the series template closely. Players control the Vic Viper through five levels, most based on levels in earlier entries, for a kind of 'greatest hits' of the series. There is a cave level (as in level 1 of the original Gradius), the mandatory Moai stage, a Gigeresque organic level, a graveyard (similar to bonus stages in the MSX and PC Engine version of the original Gradius) and a high-tech base. Besides the classic core ship in the first level, all boss enemies are entirely new.

The cycling Gradius power-up system is reused here: collected power ups advance the power meter which can be activated at any time to gain the highlighted item. The line-up includes the classic selection of speedups, missiles, dual shots, lasers, option satellites and forcefields.

The game allows players to start in any of the five levels and even to set the number of lives to a maximum of 99.