Ohio River
I've sailed, motored, and sea-kayaked on the Meldahl Dam pool of the Ohio River for the last 15 years. Like Al said about the Upper Niagra, its a beautifully kept secret with relatively few jerks (probably scared by commercial traffic) and wonderful scenery and anchorages. Yes, commercial (barge) traffic is omnipresent, but I've gotten to know the captains and pilots, and find them actually to be a comforting presence under most circumstances. My biggest problems sailing the Ohio are (1) twists and turns in the river make "steady wind" a rare thing. Hills block wind almost completely from varying stretches. Motor is desireable for meaningful "travel", and is a must for safety. (2) Not many tributaries you can explore via sailboat due to low bridges along the highways that invariably follow the shores. Other than that, the River's a great place to be on the sailboat.