Azarenka, a runner-up in Madrid the past two years, lost her temper, broke her racket and argued with chair umpire Mariana Alves. The Belarusian double-faulted five times and got in just over half of her first serves. The 24th-ranked Makarova had 60 percent first-serve accuracy.
Azarenka berated Alves after picking up a second code violation for smashing her racket in the third set.
"After all you've done, how are you still in the game?" Azarenka shouted at the official while on court.
Azarenka said she felt confused by some refereeing decisions.
"I didn't understand what happened, what I did," she said. "I was very sure that I didn't have a code violation, that's why I broke my racket."
Azarenka tried to explain the loss.
"I played more against myself, trying to prove to myself certain things, more than I was focusing on my opponent," she said.
Azarenka, who missed Indian Wells and the Miami Open in March because of an ankle injury, said she still felt rusty. She's looking forward to another clay tournament Rome before heading to Roland Garros.
"I have been making mistakes," she said. "But that's what comes after not playing for a long time. I still have another tournament before the French Open to compete in."
In men's play, sixth-seeded Tomas Berdych of the Czech Republic beat Jerzy Janowicz of Poland 6-7 (3) 6-3, 6-2, and Kei Nishikori of Japan downed Viktor Troicki of Serbia 7-5, 6-2.