On 1 August 2006 Cooke took over as number 1 on the UCI's women's world road race rankings. On 3 September 2006 she secured the UCI Women's Road World Cup for a second time after winning three world cup races in the season – La Flèche Wallonne Féminine, the Ladies Golden Hour and the Castilla y Leon World Cup Race. She also won the 2006 Grande Boucle, the women's Tour de France, by over 6 minutes. Other important wins included four stages and the overall title at Thüringen-Rundfahrt stage race and the Magali Pache Time Trial. She came third in the UCI World Road Race Championships.