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Axe-Fx II and USB in the owner's manual

Axe-Fx II USB driver for Windows and Mac

USB drivers for Mac and Windows are required and available for download here. If the USB driver is not installed, utilities such as Axe-Edit, Fractal-Bot and Cab-Lab won't recognize the Axe-Fx II.
When using the USB interface, there's no need for an additional audio interface. An external audio interface is required when connecting the analog Axe-Fx II outputs to a computer (not using USB).
A MIDI interface is not required to connect the Axe-Fx II to a computer. The Axe-Fx II itself operates as an USB-to-MIDI adapter. MIDI interfaces can still be used, and editing through a MIDI interface also is still possible.
The FX8 doesn't require a driver to connect to FX8-Edit or Fractal-Bot.
Cliff: "The driver that we supply for OS-X computers is NOT an audio driver. It is a firmware installer. The Axe-Fx II uses a "soft" USB controller. It gets it's code from the host computer. When you turn the Axe-Fx II on it requests firmware from the host. This is superior to a hard-coded controller in that updates merely require a new host image rather than reflashing the controller."

The Axe-Fx II can be used as an USB-to-MIDI interface to update the firmware on the MFC-101, using Fractal-Bot or a MIDI librarian. Walkthrough.
Cliff: "The USB Adapter feature was added for simple USB-to-MIDI functionality, specifically firmware updates for the MFC-101. It is a low priority task since audio processing is the Axe-Fx's primary usage. Latency is not guaranteed. It is not intended as anything more than a no-frills, simple MIDI adapter for non-critical tasks." source

Creating an USB connection increases CPU utilization. This is by design. If a preset uses much CPU, you may run into CPU overload problems when connecting the Axe-Fx II to a computer through USB. source and source

Cliff: "The Axe-Fx II USB is 24 bits. This is 144.7 dB of dynamic range. Full-scale is about +20 dBu. So even if your guitar is -20 dBu (-40 dB re. FS) you still have over 100 dB of dynamic range. A typical single coil pickup can easily exceed -20 dBu. A humbucker can easily exceed 0 dBu. Full-scale of 20 dBu gives you a few bits of headroom in case of very hot pickups. The self noise of a guitar pickup and associated electronics limits its dynamic range to less than 100 dB typically." And: "The digital bit depth on the USB and Digital I/O exceeds both the dynamic range of the Axe-Fx itself and certainly that of any guitar. Furthermore the bit depth is sufficient to fully capture the dynamic range of a guitar while still maintaining +20 dBu as full-scale." source
Cliff: "The hardware is incapable of doing 4x4. The only choices are 3x3 or 4x2 and Logic doesn't work with 3x3. We also had some issues with 3x3 in Windows 7 IIRC." source

High-pitched noise may be caused by a ground loop. Cliff: "The USB spec calls for grounding the cable at both ends (mistake). This can create an USB ground loop. Make sure everything is plugged into the same outlet strip." source
When experiencing problems such as dropped connections or an Axe-Fx which freezes after connecting USB, always replace the USB cable first. Example
Cliff: "An occasional flicker when hooked up to USB is not unusual. This is due to the screen redraw being interrupted by the USB thread." source
Handy tip for resolving audio dropouts in your Windows DAW