Here's a crazy one - perhaps linked to the recent automation bug. I opened up a project recently to discover that one of my soft synths was no longer working. Upon closer inspection, this is because it's getting its preset changed whenever I press Play.
 

 
I went into Preferences > Options > MIDI and everything there is switched off - specifically Zero Controllers When Play Stops and Patch/Controller Searchback Before Play Starts, 2 options which I could understand might have an effect.
 
This happens wherever I start playback - whether at the very start of the song or anywhere else. It seems to be specific to this project - it isn't manifesting in other Sonar projects with the synth in, nor when I tested it in Reaper. And it worked in this project in the past.
 
Suggestions?

Hi. Have you tried J Bridge? I have read (somewhere) that some plugs perform better with one or the other.
(I moved to X64 a few years ago, and have had next to no issues since)
All the best.

jBridge may be a bit better than bitbridge, but i remember back when i used it (up until the day Kore 2 finally went x64), i was still getting all kinds of weird problems with just about anything i would use bridging for.  i was so happy when i was able to make 32 bit plugins a thing of the past for me

Assuming the event list doesn't show a program change (and I'm assuming you recorded the file into a blank track), then I would guess bridging weirdness. As PreSonus's Wolfgang Kundrus said when asked about how to use 32-bit plug-ins in 64-bit Studio One, "tell the manufacturer to make a 64-bit version."
 
Another possibility is that a different track happens to be assigned to the same MIDI channel and is sending a program change. Also, try inserting a different, 64-bit synth and seeing if it responds similarly, or whether it's only that particular synth.

I have had this recently happen to me with a 64-bit plugins - possibly Rapture Pro, and I too had taken the check box options off like you did, but it still kept happening, so I swapped the synth out for Dim Pro, which played things properly without switching the preset.
 
Bob Bone
 

I'm not sure it's just BitBridged plugins that have these kinds of issues (I have seen things like this with 64bit plugins). 
 
It's painful to setup but you might get some clue with Piz MIDI monitor plugin (or something like it)
 
http://www.thepiz.org/plugins/?p=midiMonitor
 
You may need a MIDI loopback device as well, to figure out what exactly is happening.  Yyou might not be able to do anything about it though.  But knowing what is happening is always a good first step.

Until you find the source of MIDI data, the MIDI Event Filter MFX may help.

Well, I just fired up the project again to give these suggestions a try, and this time it's working perfectly. There were no program change events or any automation so I've no idea what happened.
 
I'd love to be able to switch to entirely 64-bit plugins, but this synth is very unlikely to ever get ported unfortunately.

I know you're a smart guy so you probably already tried this, but just in case...in Plug-in Manager, there's a parameter for "BitBridge Server." I have zero idea what it does, but maybe changing it or messing with some of the other plug-in Properties would give more consistent results.

Nope, hadn't tried that. If this problem recurs, I'll give that, and JBridge, a go before posting here.