I've been using the portable version for years, and so far I've only found two issues:
1. The installer doesn't set up shortcuts automatically. That's expected behavior, and I don't run Calibre from a shortcut anyway.
2. The individual components aren't meant to be run separately. For example, if I preview a book with ebook-viewer.exe before I decide whether to add it permanently to my library, the viewer uses default settings (screen size, etc) instead of how I set it up in Calibre.
For me, at least, the benefits far outweigh the drawbacks. I keep Calibre on a portable hard drive, which goes pretty much everywhere I go (I'm a computer geek). My library is always accessible any time I'm at a computer.
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