What type of printer? I have a Makerbot copy (CTC brand off ebay). I have the Makerbot Desktop installed which runs a background service. This blocks any COM ports for the printer, or makes them exclusive for their software. So I have to go into Makerbot and select "stop background services"
Then I can connect.
In MatterControl, in the Printer tab, under General. Make sure you have the correct Baud rate. Mines set to 115200.
One way to check which COM port Windows now uses:
In Matter Control, hit manual connect. There should be a couple of COM ports in the list. Unplug your printer USB and hit refresh. The one that disappears is your COM port for said printer. If neither disappear, you might need to install a driver for it using whatever proprietary software said printer is meant to use (in my case Makerbot Desktop). Then try again.