AC Milan will face runaway Serie A leaders Napoli in the Champions League quarter-finals, while Inter will take on Benfica in the last eight, the draw at UEFA's headquarters in Nyon established on Friday.
As a result there will be at least one Italian team in the semi-finals.
Furthermore, one of the last-four contests could be another all-Italian affair as the draw ruled that the winners of the Milan-Napoli tie will take on the team to progress from the Inter-Benfica one in the semis.
Napoli knocked out Eintracht Frankfurt to reach the Champions League quarters for the first time while seven-time European champions Milan eliminated Tottenham Hotspur.
Three-time European champions Inter knocked out Porto.
The first legs will take place on April 11 and 12, with the returns being held the following week.
Napoli coach Luciano Spalletti said only the "incompetent" could think that the draw had been kind to his side.
"I would have preferred not to take on an Italian team," Spalletti told Radio Kiss Kiss.
"Milan are the Champions League and (former club captain and current technical director Paolo) Maldini has won five alone.
"It wasn't a good draw".
Milan executive Franco Baresi said the reigning Serie A champions are in with a chance, even though Napoli are "superior to everyone" at the moment.
"Milan have history and we will play to win," he told Mediaset television.
Inter coach Simone Inzaghi said he was proud his side were among Europe's top eight sides.
"Benfica are a good team with a great tradition who won their group playing very good football," Inzaghi said.
"But we are no less than them and we are aiming to be ready order to enable our fans to keep dreaming.
"We're in for two exciting, complicated matches".
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