Pezzaiuoli, 42, succeeded Ralf Rangnick but Hoffenheim remain stuck in midtable with five games left to play.
"Obviously, it was not easy for Marco with the coach changes and the players who left in the winter," said club manager Ernst Tanner on Hoffenheim's website.
"But following the developments in the last weeks, we decided to go into the new season with another coach."
German media have reported that current St Pauli coach Holger Stanislawski, whose team are 17th and doing considerably worse than Hoffenheim, could succeed him.
Eight Bundesliga coaches have lost their jobs since the start of the year, including Pierre Littbarski who was caretaker at VfL Wolfsburg for one month, and 11 this season.
Pezzaiuoli will be added to the tally at the end of the season along with Jupp Heynckes, who has already decided he will leave Bayer Leverkusen and join Bayern.
Other victims have included former England coach Steve McClaren at Wolfsburg and former Bayern Munich coach Louis van Gaal who was sacked on Sunday.
Rangnick, now with Schalke 04, quit after four-and-a-half years during which he took the former village team from the third division to the top flight.
He was angry at the sale of Brazilian midfielder Luiz Gustavo to Bayern.
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