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I've been using Calibre Portable on an external hard drive as my main installation for over a decade, and I've never run into any problems. The biggest drawback is that for optimal efficiency you need to put your libraries in sub-folders of the Calibre program folder. And that means that if you need to keep libraries in different places, you need multiple copies of Calibre Portable. I do this myself.
On a positive note, look how many threads there are on this forum asking about backing up settings or moving the library. I have to admit I get a smug feeling when reading these posts and knowing I run an incremental backup of the entire Calibre folder every few days that hardly takes any time at all, and if I want to move the library to a new computer I just have to plug in the hard drive.
I would guess that 90% of the people who use the installed Windows version of Calibre could get by with Portable just fine. (Yes, I'm well aware that there are plenty of exceptions)
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