Like Montana Harper and others, I was plagued with this issue for many years. I've been using calibre since the beginning.. I remember worrying about the install folder becoming calibre2, and wondering if the install folder was going to change with each new version, but I digress.
The take-forever-to-open-a-book problem appeared to be entirely random, completely solution-resistant, irrespective of the size of the book file being opened. Also like Montana, I used an alternate app, FBReader, which opens anything instantly, Just in case I wanted a quick-open for a quick look.
I tried many solutions over the years to no avail, but BetterRed's seems to work. I am cautiously optimistic.
First I tried moving the cache from %appdata% to C:\CalibreCache. That didn't work; same old stuff.
So I moved the cache out of the system partition altogether, to a different partition on the same SSD. D:\CalibreCache has worked like a charm for the past three weeks. Average size ebooks open instantly! Up to 100mb they take ~3-4 seconds.The Shakespeare book, 212 MB, or its ilk, now take ~10 seconds, where they took minutes to open before.
The permissions on a non-system partition are a bit more conventional. That's the only thing I can think of. For this particular gremlin I'm full of theories, but have no answers...
Thanks BetterRed!