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Spreadbury will take charge of the all-French clash between Toulouse and Biarritz Olympique at Stade Chaban-Delmas, Bordeaux, on Saturday, 24 April.
It will be Spreadbury's 17 Heineken Cup appointment - including taking over in the 2003 final between Toulouse and Perpignan at Lansdowne Road when Chris White was injured during the match.
Williams will be on duty at Lansdowne Road, Dublin, on Sunday, 25 April, when Munster meet London Wasps.
It is the second successive season Williams will have refereed a semi-final at Lansdowne Road as he was in charge when Perpignan beat Leinster Lions there a year ago.
His 18th Heineken Cup appointment came just last Saturday when he was on duty at Thomond Park as Munster beat Stade Francais Paris in the quarter-finals.
