A meditation on death and friendship set in New England, "The Room Next Door" sees regular Almodovar collaborator Swinton as a war correspondent suffering from terminal cancer, with Moore as her friend, a successful novelist who agrees to be at her side in her final moments.
Actor John Turturro completes the leading trio in the film that translates into English what the director has been developing for more than a decade in his native language -- an increasingly melancholy cinema prone to analysing the fear of death or physical decline.
"My insecurity disappeared after the first table read with the actresses... The language wasn't going to be a problem," Almodovar has said of his latest film, which has its world premiere on the Lido Monday evening.
"People talk a lot in my films... In 'The Room Next Door' Tilda Swinton and Julianne Moore carry the weight of the whole film on their shoulders, and they are a spectacle," he said.
It is not Almodovar's first foray into English-language filmmaking. His first, the short-format "The Human Voice", premiered at Venice in 2020, featuring Swinton as an abandoned lover.
At Cannes last year, the director presented "Strange Way of Life", another short-format film, this time a gay Western starring Ethan Hawke and Pedro Pascal.
An iconic voice in Spanish cinema, Almodovar began with kitschy black comedies, such as "Pepi, Luci, Bom and Other Girls on the Heap" or "What Have I Done to Deserve This".
His breakout film was 1988's "Women on the Verge of a Nervous Breakdown", which won the award for best screenplay at Venice and the Academy Award for best foreign language film.
But with time, the more circumspect streak of the prolific Spanish director has prevailed, developing from films such as 2002's "Talk to Her" -- which won Almodovar the Oscar for best original screenplay, a rare feat for a non-English film -- and 2004's "Bad Education" to the more recent "Pain and Glory" from 2019, about his career as a filmmaker.
"Parallel Mothers", the story of two women who give birth the same day, won a best actress award for Penelope Cruz at Venice in 2021.
Almodovar's film is one of 21 competing for the prestigious Golden Lion prize, to be awarded on September 7.
