Yes that can be done. The program always gets the list of files from source and destination and compares it before copying anything.
Depending on the type of connection, such as VPN or FTP, there can be ways to speed up the building of the file list. This may be necessary if you have a lot of folders. With FTP, the latest versions of the program will try to get a recursive listing. With normal Windows networking over a VPN, you can install the "ExtremeSync Remote Service" on the remote end to help generate a fast file listing.
See also
http://www.superflexible.com/docs.htm.
If you are using FTP or other Internet protocols, you also need to test if keeping the uploaded files' modification dates works. Some servers do not allow it, in which case you may have to resort to Filename Encoding (see the Versioning tab sheet).
You can save some bandwidth by turning on the Zipping functionality. For mirroring purposes, please choose "ZIP Each File Individually". You can also copy several files in parallel. Over the Internet, between 3 and 10 files in parallel may be OK depending on the protocol used. The number can be specified on the Files tab sheet.
Finally, as an alternative to the last paragraph, you could use "ZIP Packages" with several files in each zip file, and have them unpacked on the destination machine with the ExtremeSync Remote Service. Then you can only copy 1 in parallel. See also
http://www.superflexible.com/remoteservice.htm.