A separate profile is required for each remote. You can migrate a profile from one remote to another but support for the old remote is lost. (See replace remote on the main page.) I've had problems like repeated software crashes when trying to upgrade a remote within the same profile. Custom key mappings may also be lost. The software claims it will copy setting from and existing profile to another, new one. It didn't seem to work but a Logitech CSR was able to. All custom key mappings are lost when profiles are copied. For me, that meant a lot of reprogramming. I'm still finding missing custom keys, months later. Upgrading remotes and adding new ones is an area where the Harmony software is very badly written.
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