I have been using DXLabs for my log for years (after giving up on HDR for many reasons). My Elecraft K3s was the first radio I used (I love its full break-in on CW). My Yaesu FTDX-101MP followed quickly (fairly typical COM port setup). But I never added in my FlexRadio 6600M until today.
The process turned out to be very simple and completely documented in Dave’s excellent Wiki. I just made sure to start SmartSDR running, then followed the instructions. Within a couple of minutes, I was connected.
I immediately noted that the sensitivity of the Flex dropped — like another radio had been added (and in fact, that’s what happened). I shut down SmartSDR (killing the panadapter on the PC screen) and everything was back to “normal”. After that point I didn’t have to restart SDR, even as I started and stopped DXLabs or power-cycled the PC. I haven’t tried shutting the FlexRadio down yet (bitter experience has taught me that shutting the Flex down can sometimes do nasty things, like corrupt an internal SD card), so perhaps the SDR software needs to be running to establish the initial connection, and isn’t required subsequently (at least for DXCommander and DXKeeper’s purposes).