Sadly, it only seems to work with interfaces with a single input. I have an old Apogee Jam (USB) that works fine with Rocksmith. But I also have a much better, lower latency, 4 input PreSonus Quantum 2 Thunderbolt 2 interface that doesn't work. Which is very disappointing because it is the only software I've found on a Mac that doesn't work with the Quantum interface.