Williams, whose status as world number one is under attack from several fronts, delivered a message that she will not be surrendering the top spot without a fight, needing just 63 minutes to dispatch the 29th-ranked Russian.
Germany's Angelique Kerber and Spain's Garbine Muguruza, who have both beaten Williams in slam finals this season, along with Poland's Agnieszka Radwanska, will all be eyeing the number one ranking should the American's bid for a 23rd grand slam title stall.
Williams has owned the number one spot since Feb. 18, 2013 and will extend her streak to 186 consecutive weeks by the end of the U.S. Open fortnight, tying the WTA record held by Steffi Graf.
Back on Arthur Ashe Stadium court for the first time since a shock loss to Italy's Roberta Vinci in last year's U.S. Open semi-finals, Williams made quick work of Makarova to follow the lead of her sister Venus.
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Sixth-seeded Venus had provided the opening act for sister Serena when she outlasted Ukraine's Kateryna Kozlova 6-2 5-7 6-4 before turning over the Arthur Ashe Stadium court to her top-seeded sibling.
The Flushing Meadows spotlight is once again firmly fixed on Serena as she chases an Open Era, record smashing 23rd slam title with concerns over her right shoulder, believed to be a factor in her third-round singles loss at the Rio Olympics.
FASHION STATEMENT
As always at the U.S. Open, what the world number one was wearing attracted as much attention as her performance. Williams sported a black tennis dress with cutouts revealing her muscular shoulders.
"It's a part of the design," explained William. "It's just the latest and greatest accessory.
"It also is functional, so I think that helps me, especially with my shoulder problems that I've been having."
The 34-year-old American took something off her big serve, but showed no signs of distress as she blasted 12 aces past Makarova, a player who on occasion has given her problems, beating her in the fourth round of the 2012 Australian Open.
"I didn't hit them as hard as I normally hit them," she said about her serves. "I just went for more placement. I didn't go for the big 120s (mph), just the regular."
"I knew today I needed to be focussed," said Williams. "She goes deep in majors. She knows how to play big matches on big courts. She's not intimidated."
As usual, history beckons Williams who is bidding for a seventh U.S. Open victory that would surpass the Open Era record she shares with Chris Evert.
But whether it is the world number one ranking or another record at stake, Williams had the same answer.
"I don't answer those questions," flatly stated Williams, who will next face American wild card Vania King, a 7-6(2) 6-3 winner over Germany qualifier Antonia Lottner.
(Editing by Larry Fine)
