The big-serving Querrey proved too strong for the 21-year-old Harris, who is the second-highest ranked South African and a rising star who made it through qualifiers to compete in last year's US Open and this year's Australian Open.
Harris had no answer for Querrey's blistering serves and punishing groundstrokes unleashed from the outset on the black hard courts of the Nassau Veterans Memorial Coliseum.
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Querrey will next face either Croat Ivo Karlovic or Moldovan Radu Albot, who play their first round match on Wednesday.
Querrey's win capped a good day for the hometown Americans as Louisiana native Ryan Harrison's pinpoint serving sent Canadian Peter Polansky packing in a 6-3 6-4 route earlier in the day.
Murray begins US Open prep with quickfire win over Querrey in Newport
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