Mainframe may refer to either of the following:
- Mainframe computer, large and powerful data processing systems
- Mainframe Entertainment, a Canadian computer animation and design company
- Mainframe (band), a 1980s Electropop band
- Mainframe is the name of two fictional characters from Marvel Comics:
- Mainframe (comics) appears in the series A-Next
- Mainframe appears in the Guardians of the Galaxy series; see Vision (Marvel Comics)#Mainframe
- Mainframe (Transformers) is an Autobot character in the Transformers series
- Mainframe (G.I. Joe), a fictional character in the G.I. Joe universe
- A character from the game Gunman Chronicles
- Mainframe is the city in which the CGI cartoon ReBoot takes place
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