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Third in the table and Champions League semi-finalists last season, pundits in Germany had predicted a tougher ride for Leipzig this year after they sold star striker Werner to Chelsea.
Yet Julian Nagelsmann's side were at their free-flowing best as they started the new campaign in front of 8,500 fans, chalking up 23 shots on their way to a deserved win.
"It was simply amazing to play in front of our fans again. We put on a great performance for them today," said Emil Forsberg, who opened the scoring from the penalty spot and set up another for Amadou Haidara.
"To beat the best teams you have to give 100 percent. If we're as motivated as we were today, we'll be among the top sides again."
Leipzig have now scored 16 goals in their last three games against Mainz, who are preparing for another relegation dogfight this season.
"It's no secret that we would like another striker because the season will be a demanding one, but our forwards did their job well today," said Nagelsmann.
"If we had taken all our chances, we could have scored seven or eight."
The home side burst out of the blocks, with both Dani Olmo and Marcel Halstenberg coming within inches of taking the lead in the first few minutes.
The opener came after just a quarter of an hour, as Olmo was tripped by Leandro Barreiro in the box and Forsberg slotted home the resulting penalty.
Danish international Yussuf Poulsen then sent a fizzing shot over the crossbar before doubling the lead with a looping header on 21 minutes.
After Forsberg hit the post on the half-hour mark, it seemed a rout was on the cards.
Jean-Philippe Mateta beat the offside trap just after the break to bring Mainz back into the game, but Haidara linked up with Forsberg just a few minutes later to make it 3-1 and put Leipzig out of reach.
Despite the commanding display Nagelsmann warned that his side would have to up their game when they travel to Bayer Leverkusen next weekend.
"They are a tough opponent, so we will have to be that little bit better," he said.
Leverkusen, who have also lost a star player in Kai Havertz to Chelsea, began their campaign with a goalless draw at Wolfsburg in Sunday's other game.
Wolfsburg had two clear chances to take the lead in the first half, US international John Anthony Brooks heading over the bar before Wout Weghorst forced a smart save from Lukas Hradecky.
After the break, Wolfsburg forward Admir Mehmedi had a goal ruled out for offside against his former club, while goalkeeper Koen Casteels twice kept out the visitors at the other end.
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