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Another good reason to have a separate domain is so that your main mail servers don't get overloaded with bounce messages, people hitting reply, etc.

Good point. I could have both notify@notify.startup.com and me@startup.com. That could mean I'd have two separate mail servers.

I'm mostly worried about signup/+3 day/+7 day notifications to new users from damaging the spam reputation of me@startup.com when I attempt to email important people to discuss e.g. biz dev deals.

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