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The original ending of the script featured a cameo appearance by Dutch Schaeffer (Arnold Schwarzenegger) from the first film. After defeating the Super Predator, Quinn, Casey, and Rory are resting when a helicopter lands and Dutch, described with a "face haunted; etched by pain," steps out and tells the three of them that they have to come with him (when Rory asks if this includes him, Dutch replies "Especially you"). This would likely have been the set-up for a major role for Dutch and Rory in a sequel. Schwarzenegger read the script but turned the offer down, as he didn't want to have a mere cameo.
When the Predator grabs its mask from the display case, the original Predator mask from the 1987 movie is briefly seen right next to it.
Although no mention is made in the movie, the character Keyes played by Jake Busey is the son of Peter Keyes, the government official from Predator 2 (1990) who died during the hunt for the Predator. Peter Keyes was played by Gary Busey, who is Jake's father in real life as well.
The film was originally conceived as a reboot of "Predator" until Shane Black came aboard and confirmed he would be making a sequel instead, as he wanted to continue to explore the "Predator" mythology.
The film was directed and co-written by Shane Black, as a sequel to Predator (1987), Predator 2 (1990), and Predators (2010). Shane Black played Hawkins in the original film.
Shane Black wrote Thomas Jane's character Baxley with Tourette's syndrome because Black himself has Tourette's.
Shane Black: [Disarming a gunman] Quinn McKenna takes a gun out of Casey's hand while she holds him at gunpoint. Black's screenplays often feature such scenes, e.g. The Last Boy Scout (1991), The Long Kiss Goodnight (1996), and Kiss Kiss Bang Bang (2005).