Prop Adam Jones, regarded as one of the finest scrummagers in world rugby, will miss games against Argentina, Samoa, New Zealand and Australia due to a knee problem, the Welsh Rugby Union announced on Friday night.
Jones went off early in the second half during the Ospreys' Heineken Cup defeat against Leicester on Sunday and now faces a lay-off of between six and 10 weeks.
The Wales squad, under interim head coach Rob Howley's direction, leave for a training camp in Poland this weekend.
Jones, 31, had been due to be part of those pre-autumn preparations, but he will now concentrate on regaining full fitness prior to Wales' RBS 6 Nations title defence.
The WRU said Jones will be regularly assessed to establish an accurate timescale for his return to playing. He was reviewed by an orthopaedic surgeon today.
Jones, who has won 83 caps and played in two Tests for the British and Irish Lions on their 2009 South Africa tour, originally injured his knee last month.
But his early exit against Leicester set alarm bells ringing, and concerns over his fitness were sufficient for Wales to draft uncapped Scarlets prop Samson Lee into their squad as cover for Jones in Poland.
A decision on whether Lee now joins the autumn Test squad permanently, or another player is called up, will be made at a later date.
Apart from his immense value to Wales, Jones could also be considered a prime candidate to tour Australia with the Lions next summer.
That squad will be headed up by Wales boss Warren Gatland, which is why Howley is in charge for Wales' autumn Test programme and the Six Nations campaign.
Wales' Six Nations opener is against Ireland in early February.
Jones' absence is the second setback to hit Wales this term.
Flanker Dan Lydiate, player of the tournament in last season's Six Nations, suffered a serious ankle injury during a RaboDirect PRO12 game against Edinburgh.
It is thought he is unlikely to regain full fitness until after the Six Nations, although like Jones, he should be fit and available for the Lions tour.
Wales start their autumn programme against Argentina on November 10 before facing Samoa six days later.
They then meet world champions New Zealand on November 24 before concluding the autumn programme against Australia seven days later.
Wales have not beaten the All Blacks since 1953, while they will meet the Wallabies for the first time since losing all three Tests Down Under earlier this year.
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