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I'd add them to a list in the lead database and label it as suppression; then build your smartlist for the send. Marketo will add them to your database since you're uploading them. Another alternative would be to run a smart campaign and mark these people as 'suspended' which will automatically remove them from every subsequent send.
Thanks Kristen. Can you explain how I add the suppression file to a list in the lead database and label it as a suppression? If I do this, and later build a smartlist for a new send to the whole database, will the smart list automatically exclude the leads labeled suppression?
You can either run the list through a smart campaign with the flow step of "marketing suspended" or just remember to add member of list not in " " for every send. Since it sounds like this is an on-going suppression list, you should probably just mark them as suspended so you don't have to remember to remove them every time.