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The best virus/malware/spyware- protection is using an adblocker and a flash/scriptblocker together with some good, oldfashioned common sense. Oh, and displaying your email as text-only helps as well.
That said, I'm using an oldish version of Avira antivirus (with up-to-date definitions, of course) and have never had any issues with Calibre. I do seem to remember Norton flagging random software for what seems like grins and giggles, though.
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