Consider this situation: There’s a critical VB6 desktop application running on a production box. There is a possibility of installing a .NET application that queries the same DB that the VB6 application queries, which is an SQL Server 2000 DB. The VB6 application also depends on third-party ActiveX controls (registered .ocx files).
The concern is – will the .NET Framework installation replace any files or break the VB6 runtime in any way. In other words, can we safely assume that an installation of the .NET Framework is completely independent of any previous VB6 installations and will not interfere with the running application?
If this is critical, clone the production system and install the .NET Framework on the clone first to test if there is any interference with your new application.
As Randolpho already said, the .NET Framework installation is independent from the VB6 runtime. But be aware that you must reboot your production server, and that you should also check whether your new .NET applications interferes with the legacy VB6 application.
In general, it is good practice for critical systems to have such a staging server for testing and Q&A that mirrors your production environment.