Per Una, which was launched in 2001 as a joint venture between M&S and Next Plc (LON:NXT) founder George Davies, had been largely successful in attracting female shoppers under the age of 35 with Italian-inspired designs.
It generated about £750mln for M&S at its peak.
But now Per Una is one of several brands to be put under review by chief executive Steve Rowe as part of a cost-cutting drive following ongoing struggles in the clothing arm.
M&S bosses are understood to be concerned that Per Uno has failed to keep up with more fashionable online rivals and cheaper high street alternatives, the Mail on Sunday reported.
Other brands facing the chop include Autograph, Limited Edition and Blue Harbour but Per Una is most at risk, the newspaper said.
Brands Indigo, North Coast and Collezione have already been ditched.
A spokesman said: "We’re continuing to review our sub-brands, some of which have lost their identity in recent years, in order to provide great value choices for stylish wardrobe essentials to our customers."
Non-food sales fell 1.9% on a like-for-like basis last year with M&S blaming a tough retail market.
The company’s food division, which has kept M&S going strong despite lacklustre clothing sales, has also started to show signs of weakness with like-for-like sales falling 0.3% last year.
M&S plans to close 100 UK stores by 2022 as part of a restructuring plan to reduce the amount of space devoted to the clothing and home arm.