I have heard of this happening a couple of times before but also in the Arduino ide. 

Maybe Arduino have found how to fix it I will look over the next few days

In the meantime please give the following info.

Which Arduino version are you using?

What is the name, date and time of the usb driver for the Arduino board (window device manager)

Which 2560 do you have R3?

Thanks

Oh, so this sounds like a windows usb issue. I believe that the latest 2560 boards include a patch/solution for this problem. 

I know it works via Arduino IDE but ...

Visual Micro uses avrdude.exe to upload so does not access the port directly, it is the 2650 or avrdude that is leaving the port in a poor state. 

It is possible that Visual Micro could alter timings slightly to prevent the problem but I have never been able to replicate and it is a documented problem that also happens to the Arduino ide sometimes (or used to prior to the latest 2560 bootloader)

What is the name and date of the usb driver?

Once solution I heard about is to disable and re-enable the usb driver, another is to switch on "RTS on Close" which is a property of the usb driver.

If this continued to be a problem then you  can switch on "File>External Editor" in arduino ide. This allows the sketch to be open in both Arduino and VS/Atmel, use Arduino for upload.

Sorry can't be more specific

Having re-compared the arduino ide code with visual micro...

In the Arduino Ide there was a 100ms delay in the routine that forced the Arduino to reset prior to upload. This delay was shorted in the Visual Micro code but has been corrected to match the Arduino Ide code for the next release.

Please follow the project on our codeplex download site so that you get an email when the next release happens. 

I think this will fix the problem for you but there are also some additional config properties in the next release which I won't publish unless they are needed for testing. The idea being we just do what the Arduino Ide does and keep things clean and simple.

Thanks again for the report

I installed 1308.18 and for now no problems, but have very little hobby time at the moment. I'll keep you posted.

If I detach (unplug the USB cable) my MEGA while a serial connection is active and reattach the board I'm in trouble.
Although closing the serial window and detach and re attach solves it. Not sure if this is the same issue I have had earlier.

EDIT: to be more precise, I need to close the serial window before re attaching the board.

For now I have not yet found a need to restart VS to get it to work again. Before I needed to restart VS quite a lot when using my MEGA.

Also it seems that if I connect my Arduino prior to starting VS2010 the first upload always fails. The led on my board just blinks every second or so, not the burst of flashes one would expect during upload. Unplugging and replugging solves it.

Hmmm, I experienced the same problem I described in reply#11 using Arduino.exe instead of VisualMicro