hhuffman

This will depend on the Input Sensitivity of your Guitar Amp's FX Loop. Try Helix's Settings both ways. You won't damage your guitar amp. It will just be louder or lower. Go with the setting that is closer to when you are using your amp directly.

According to the Quick Start guide I should be setting it to Instrument, but using the 4 cable method it sounds much louder (better?) in Line. I'll play around a bit and maybe there is a benefit to Instrument, but initially it sounded like Line was the way to go. 

Gear Head and the rest of the responders.....Thank you so much for your great explanation of this setting. I got here through a quick Google search of the Helix 4 cable method and you've answered basically the same question for me as the original poster had. 

Now....if I want to use this cable method all of the time, is there a way to set that up in Global so that it ALWAYS puts my user presets in the 4 cable method, or do I have to add the send/receive block every time I make a preset?