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No, as long as you do it right. All books and per-library settings, for instance custom columns, saved searches, virtual libraries, etc. are saved in the database and will be there on any computer/calibre installation that you open that library in.
All general calibre-level settings, for example conversion defaults, device configuration, custom plugins, known libraries, fill-in (search, choose library dialogs) history, and other stuff are stored in the configuration folder. See Preferences ==> Advanced ==> Miscellaneous, "Open calibre configuration directory" to find it, or go to "%APPDATA%\calibre" in the File Explorer. This will need to be copied over to the settings folder in calibrePortable. It will work fine there.
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