Kate and Gerry McCann said her absence is acutely felt by the family, including by younger siblings Sean and Amelie, with the words "If only Madeleine was here too" a regular occurrence.
In a Christmas message written on the Find Madeleine website, Mrs McCann thanked people for their support and said they remain hopeful that the Portuguese authorities will reopen the case.
Madeleine was nearly four when she vanished from her family's holiday apartment in Praia da Luz in the Algarve on May 3, 2007 as her parents dined at a tapas restaurant.
Her parents have campaigned for information on her whereabouts, battling for a review by the police, which has now been under way for more than 18 months.
Mrs McCann wrote: "As we approach the end of another year, we'd like to thank everyone again for their amazing support.
"It is both heart-warming and reassuring to know that after all this time Madeleine still remains in so many people's hearts and minds."
She said they had been "really impressed and greatly encouraged" by the work done on the review, which was showing there are "definitely many stones yet to turn".