It was the 18-year-old Scot's first match against a player ranked in the world's top five, and he managed to push Safin, the fourth seed, before being shown the door in his debut appearance in a Masters Series event.
Having raised his ranking to 132 by winning his second Challenger title of the summer and his career in Binghamton on Sunday, Murray went from the lower level ATP event in New York state to Cincinnati with a wild card.
He made the most of his debut with a first-round win against the American Taylor Dent, 7-6, 7-6, but was unable deal with the foibles of Safin, the reigning Australian Open champion.
Murray had treatment to his right shoulder before Safin served out the opening set in the 10th game. Seven weeks of tennis and his opponent's heavy shots may have contributed to the Scot's discomfort.
After an edgy start to the match, in which he lost the first two games and had to save a break point before holding in the third, Murray began to fight back with enterprising shots and smooth footwork. Having broken back to 3-3 Safin losing his serve from 40-0 Murray then played a sloppy service game, double faulting twice to be broken again for 4-3. Safin held in the next game and Murray had to save two set points in the ninth game before delaying the set by holding serve and calling for the trainer.
Safin, who had not won a match since Wimbledon until he came to Cincinnati, having struggled with a knee injury, had time to reflect on the opening games and reassure himself that his dodgy left knee was not worse than a niggle, before converting his third set point.
Murray, far from disheartened after losing the set, began the second set in lively fashion, winning the opening two games. Even though Safin fashioned a break point in the third game, Murray saved it with a drop shot and held for three love. The final set was a reversal of the second, with Safin snapping into form and Murray beginning to wilt. A loose service game put Murray 2-0 down and he only held serve once in the fourth game, making too many errors to trouble the Russian further.
Two double-faults in the sixth game put Murray 5-1 down and Safin moved into the third round by holding serve in the next game and finishing with an ace.
With Greg Rusedski and Tim Henman also winning their opening matches in the tournament, Britain started yesterday with three representatives in the second round of a Masters Series event for the first time.
But the day ended disappointingly, with Rusedski, losing to Lleyton Hewitt, of Australia, 1-6, 7-5, 6-4 after a double-fault on match point, while Henman, who defeated Nicolas Massu, of Chile, 6-2, 6-1, went out 6-4, 6-4 to Juan Ignacio Chela, of Argentina.Reuse content