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Eli Raphael Roth was born in Newton, Massachusetts, to Cora (Bialis), a painter, and Sheldon H. Roth, a psychoanalyst, psychiatrist, and clinical professor. His family is Jewish (from Austria, Hungary, Russia, and Poland). He began shooting Super 8 films at the age of eight; after watching Ridley Scott's Alien (1979) and vomiting, and deciding he wanted to be a producer/director. With his brothers and friends, ketchup for blood, and his father's power tools, he made over 50 short films before attending film school at NYU, where he won a student Academy Award and graduated summa cum laude in 1994.

Eli worked in film and theater production in New York City for many years, doing every job from production assistant to assistant editor to assistant to the director. At the age of 20, Roth was development head for producer Fred Zollo, a position he soon left to write full time. To earn a living, Roth did budgets and schedules for the films A Price Above Rubies (1998) and Illuminata (1998), and often worked as a stand-in, where he could watch directors work with the actors. In 1995, Roth co-wrote the script that would eventually become Cabin Fever (2002) with friend Randy Pearlstein, and the two spent many years unsuccessfully trying to get the film financed. Roth left New York in 1999 to live in Los Angeles, and within four months got funding for his animation series Chowdaheads (1999). Roth and friend Noah Belson (Cabin Fever (2002)'s Guitar Man) wrote and voiced the episodes, which Roth produced, directed, and designed. The episodes were due to run on WCW's #1 rated series WCW Monday Nitro (1995) but the CEO was fired a day before they were scheduled to air, and the episodes never ran. Roth used the episodes to set up a stop motion series called The Rotten Fruit (2003) which he produced, directed, and animated, as well as co-wrote and voiced with friend Belson. Between the two animated series, Roth worked closely with director David Lynch, producing content for the website davidlynch.com.

In 2001, Roth filmed Cabin Fever (2002) on a shoestring budget of $1.5 million, with private equity he and his producers raised from friends and their family. The film was the subject of a bidding war at the 2002 Toronto Film Festival, eventually won by Lion's Gate, instantly doubling their investors' money. It went on to not only be the highest-grossing film for Lion's Gate in 2003, but the most profitable horror film released that year, garnering critical acclaim from The New York Times, Rolling Stone, Empire Magazine, and such filmmakers as Peter Jackson, Quentin Tarantino, and Tobe Hooper. Roth used the film's success to launch a slew of projects, including The Box (2009), a horror thriller he co-wrote with Richard Kelly. In May 2003, Roth joined forces with filmmakers Boaz Yakin, Scott Spiegel, and Greenestreet Films in New York to form Raw Nerve, LLC, a horror film production company.

In 2014, Eli married Chilean model and actress Lorenza Izzo.

Cate Blanchett, Jack Black, and Eli Roth in The House with a Clock in Its Walls (2018)

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