Providing a network log will help make this bug actionable. 

Please see https://sites.google.com/a/chromium.org/dev/for-testers/providing-network-details

I was able to have this appear on my laptop.  Attached is the requested network details for then this happens.  The tab this occurred on was attempting to load https://sailormoonevents.org and a 500 appeared.  At the same time, the site loaded with no issues in an incognito window.

Deleted: net-internals-log.json 323 KB

net-internals-log.json 323 KB View Download

Thank you for providing more feedback. Adding requester "jkarlin@chromium.org" for another review and adding "Needs-Review" label for tracking.

For more details visit https://www.chromium.org/issue-tracking/autotriage - Your friendly Sheriffbot

Thanks for the net log.

That it works in incognito mode and after changing profiles suggests that it's related to your extensions. Try running with them disabled (or stay in an incognito for awhile) and see if it continues to occur. Privacy Badger for one will add extra headers to your requests that might cause servers to refuse them.

Thank you for looking into this.  For the others who reported this to me, I will have to see if I can confirm potential extensions.  However in my case, I also have Privacy Badger running in incognito mode where the same site was loading fine while it was having the error in my main profile.  I will definitely look into any potential issues on servers I control in regards to extra headers being added possibly affecting this.  It's frustrating that this occurs with no known rhyme or reason currently, hopefully we can get this figured out on one of our ends.

Thank you for providing more feedback. Adding "Needs-Review" label for tracking.

For more details visit https://www.chromium.org/issue-tracking/autotriage - Your friendly Sheriffbot

I just had a colleague recreate the issue on her workstation.  I can conform there are no extensions that manipulate headers on her machine.  A site reported a 500 error on her main profile, but loaded fine incognito as well as in Firefox.  She uses Windows 7 Version 6.1 (Build 7601: Service Pack 1), Chrome Version: 49.0.2623.112 m.

I took a look at the net-log. The only header modification by extensions was adding "dnt: 1". Request looks pretty normal otherwise.

Things you could try:
1) Try capturing netlogs of both a working and non-working session and compare them.
2) Instead of restarting the browser, try clearing cookies for that site and see if the error goes away.

Thank you for the suggestions for better troubleshooting.  I determined a link between the sites this behavior was noticed, which was the iThemes Security plugin for WordPress.  I reported my findings to their support forum with no response.  When looking for any potential earlier issues, I found a support thread from over a year ago - https://wordpress.org/support/topic/ithemes-security-throwing-semi-random-internal-server-500-error?replies=13 .  Basically, it seems like someone figured out at that point that iThemes Security is doing something with the handling of cookies causing the 500 to sometimes appear, also only on Chrome.  Sadly, it seems that we'll never find out exactly what, as staff never acknowledged the issue back then either, even with more information at the time.

I believe this issue would be safe to close.  With no response on their end for so long, and all other moving parts I've contacted (including here) at least trying to give advice fro troubleshooting, I would place the fault fully with them at this point.  I've gone ahead and replaced this plugin with the WordFence Security plugin on the known sites with the issue, and they have yet to resurface.

This was definitely one of the oddest issues I have come across.  I wish a solid conclusion could have been reached, but I'm very happy to finally bring this to a close.  Thank you to all here who helped me get to the bottom of this.

Happy to help.