I can't recall exactly but I think in my case it also happened if I completely powered down the server, the only way to make the USB drive boot again was to change it to another port, let's see what @Austin Detzel says.
I also recall that it was not a problem related to Unraid or its booting drive. To isolate the problem I tried with other booting systems (Ubuntu and PassMark's Memtest) and I had the same problem, they would boot fine the first time but they would refuse to boot again unless I changed the USB drive to another port.
By the way, this seems to be a known issue:
I vaguely remember something about Fast Boot so I would recommend @Austin Detzelto test the following (in order):
1. Disable "Fast Boot" and try again
2. If that doesn't work, in "Settings > Advanced > USB Configuration" set "XHCI Hand-off" to "Disabled" and "Legacy USB Support" to "Auto" and try again
3. If it still doesn't work, try to tweak the booting options to enable UEFI booting/Secure Boot and be sure that you're booting the Unraid USB drive in UEFI mode (rename "EFI-" folder to "EFI").
I can't restart my server right now because I'm rebuilding Parity but if you still have problems let me know and I will check what my settings are in the BIOS so you can compare and see if copying them solves your problem.
