Scotland centre Alex Dunbar faces a race against time to be fit for the Rugby World Cup beginning in September.
The midfielder damaged his knee during Thursday's training session and a hospital scan revealed he had ruptured his anterior cruciate ligament.
The injury requires surgery, and a six-to-nine-month recovery period.
Dunbar, 24, was set to start on Saturday; Edinburgh centre Matt Scott has been promoted in his place.
With 14 caps, the Glasgow Warriors player has been an integral part of head coach Vern Cotter's squad, starting the past six matches under the New Zealander.
Dunbar's strong-running style, soft hands and prowess at the breakdown for club and country have won many plaudits this season, and he has made over 100m with ball in hand during Scotland's three Six Nations fixtures to date.
The centre joins props Jon Welsh and Gordon Reid, second-row Richie Gray, scrum-half Henry Pyrgos, stand-off Duncan Weir, midfielder Duncan Taylor and wingers Sean Lamont and Sean Maitland on the treatment table.
His injury opens the door for Scott, who thus far in the tournament has been restricted to appearances from the bench, and club-mate Peter Horne, who filled in at stand-off against Italy with Finn Russell suspended.