How to fix Different format than specified by the file extension in Excel 2010

After upgrading to Excel 2007 or Excel 2010, an error specifying the file you are trying to open .xlsx is in a different format than specified by the file extension when you try to open an excel document:

The file you are trying to open .xlsx is in a different format than specified by the file extension. Verify the file is not corrupted and is from trusted source before opening the file. Do you want to open the file now?

This error occurs when you’re trying to open an XLS file (Excel 2000-2003) with Excel 2007 or Excel 2010.

Quickest way to solve this error (registry)

The quickest way to solve this problem is to insert a registry key. This suppresses the notification.

For Excel 2007, create this key in your registry:

[HKEY_CURRENT_USER\Software\Microsoft\Office\12.0\Excel\Security]
“ExtensionHardening”=dword:00000000

For Excel 2010, replace 12.0 for 14.0, as you can see below. Create the following key in your registry:

[HKEY_CURRENT_USER\Software\Microsoft\Office\14.0\Excel\Security]
“ExtensionHardening”=dword:00000000

The step-by-step instructions are as follows:

1. Click Start, click Run, type regedit.exe and press ENTER. This will open your Registry. (Do you have Windows 7 or higher? Then run registry editor as administrator)
2. Navigate to HKEY_CURRENT_USER\SOFTWARE\MICROSOFT\OFFICE\12.0\EXCEL\SECURITY
   (or 14.0, in case of Excel 2010)
3. In the right window, Right click and choose New -> DWORD
4. In the Name field, type “ExtensionHardening”  (without the quotes)
5. Verify that the data has the value “0”
6. Click OK. Done!

I advise the steps above to solve the problem. Although it is not the safest option.

Easiest way to solve this error (GUI)

The easiest way to solve the error The file you are trying to open .xlsx is in a different format than specified by the file extension is to use the Options screen in Excel 2010. Follow these steps to disable the warning message:

1. Open Excel 2010. Click on File, and go to Options.
2. Click on Trust Center at the left. Then click on Trust Center Settings in the right window.
3. In the new window Trust Center, click on Protected View on the left side panel
4. Uncheck all options:
   1. Enable Protected View for files originating from the Internet
   2. Enable Protected View for files located in potentially unsafe locations
   3. Enable Protected View for Outlook attachments
5. Click OK (2x). Done!

Back in 2008 I advised people to properly configure MIME Types to resolve this issue. However the issue does not occur in later versions of Office (2013, 2016 and so on). Therefor it doesn’t feel necessary anymore. This is what I stated 10 years ago: If you want a more constructive way, you should define MIME types and associate them with extensions.
Do you use a Document Management System like Sharepoint or Livelink? Try adding these:
.xls = application/msexcel
.xlsx = application/vnd.openxmlformats-officedocument.spreadsheetml.sheet

Fix The file you are trying to open .xlsx is in a different format than specified by the file extension with Group Policy

As an administrator you may want to consider the option to deploy the registry settings with a Group Policy Preference. I have not written a step-by-step guide to do this yet, but you may find this blog post about deploying WIFI-profiles with GPO Preference interesting and helpful.