Vettel, who started from pole at the inaugural race in Austin last year, will be favoured to do so again on Sunday after lapping the Circuit of the Americas in a best time of one minute 36.733 seconds.
The 26-year-old German, who clinched his fourth successive title in India last month, will be chasing a Formula One record eighth win in a row on Sunday at the spectacular circuit carved out of the south Texas scrubland.
Vettel's Australian team mate Mark Webber was the only other driver to dip under 1:37.00, crossing 0.203 behind in a practice session run in overcast conditions.
Britain's Lewis Hamilton, a winner in Texas last year for McLaren, signalled he is ready to defend his U.S. title with Mercedes after posting the third best effort ahead of Germany's Nico Hulkenberg in a Sauber.
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Frenchman Romain Grosjean, yet to win a race, was fifth fastest for Lotus followed by McLaren's Jenson Button, who will go into qualifying later on Saturday with a three spot grid penalty for passing under a red flag during Friday's opening practice session.
Ferrari continued to struggle to find pace on the twisting circuit, with Spain's former-world champion Fernando Alonso well down the timing chart in 11th with his Brazilian team mate Felipe Massa in 17th.
(Editing by Josh Reich)
