Spieth, who led from start to finish last year, fired a flawless 66 to become the first player in tournament history to hold the outright lead in five consecutive rounds at Augusta National.
But despite dropping two shots in his last three holes to card an opening 70, McIlroy was optimistic about his chances of claiming a first green jacket to complete the career grand slam.
“He’s very, very comfortable here,” McIlroy said. “You look at the way he played in 2014 and 2015 and look at what he’s done this year; it’s a golf course he’s comfortable on and he’s going to be tough to beat this week.
“I feel I’m going to have to play good golf, but I feel there’s enough good golf in me so that I can reel him in over the next 54 holes.”
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Spieth’s 66 gave the 22-year-old a two-shot lead over Ireland’s Shane Lowry and New Zealand’s Danny Lee, with Paul Casey, Justin Rose, Ian Poulter, Sergio Garcia and Soren Kjeldsen all a shot behind in pursuit of a first European win since 1999.
Danny Willett was alongside McIlroy on two under after making his only bogey of the day on the 18th, but world number one Jason Day finished level par after slumping to a back nine of 41, which included a triple bogey on the 16th.
“I would have signed for two under and not even played the round, knowing the conditions that were coming up,” said Spieth, who is a record 29 under par for his nine competitive rounds in the Masters. His position after each of those rounds reads 12-3-1-2-1-1-1-1-1.
“I think that everything that we do is building up around the major championships, and so we are trying to peak this week. We’ve done as good a job or better at this point than we did last year up until now. We try and get everything obviously firing to where I don’t have to think about much this week and just play the golf course.
“Obviously if we continue what we’re doing right now and it goes our way, then that would be a fantastic statement to have made. But I feel great about the way things have been.”
Lowry was keen not to get carried away by the prospect of winning a first major title despite a superb 68, adding: “’Winning a major obviously is a big deal, it’s something that you want to do as a golfer and it’s nice seeing my name up there. But it’s a long way to go yet, especially around this place.
“You’re only ever a bad bounce away from a bit of a disaster, so you’ve just got to keep your head on. You’ve just got to keep trying to hit good shots and hit towards your targets and hopefully make a few putts, and that’s all I’m going to try and do.’’