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The 4x4 edition received a four-star overall rating, with a lower rollover rating than the 4x2.

Ford's redesigned F-250 Super Duty pickups have received mixed results in the National Highway Traffic Safety Administration's New Car Assessment Program.The rear-wheel drive crew-cab edition received the highest crash rating of five stars, making it the "safest Super Duty ever." The pickup received five stars in the frontal- and side-crash scenarios, with a four-star rollover rating.

The equivalent 2016 model received a four-star overall rating, with a lower frontal-crash score.

The 2017 4x4 crew cab edition maintained its four-star overall rating, despite the redesign and improved frontal-crash score. The 4x4 drivetrain has a lower rollover rating of three stars.

Ford suggests the redesigned Super Duty's mix of aluminum and high-strength steel results in more local frame stiffness at certain locations to improve occupant protection, with the added benefit of a 350-pound reduction in curb weight.