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The safest method to use is Mac App Store only. You can control the settings for Gatekeeper in System Preferences > Security & Privacy > General, under the section "Allow applications downloaded from:" Software that can harm your Mac, or have a very bad reputation:
#WHAT IS CLAMXAV FOR MAC#
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The best protection you can get, however, is common sense. Hearing about malware on the Mac may make you feel more cautious and make you think you have a need to install anti-virus (AV) software.