He was America’s first known serial killer and built a "murder castle" to slay as many as 200 people.
But could HH Holmes also be the real identity of another notorious murderer?
The killer's great-great-grandson Jeff Mudgett believes his ancestor was also Jack the Ripper, who terrorised London's East End between August and November 1888.
"I am the descendent of the Devil," he says "My great-great-grandfather engineered a death factory in the late 1800s that claimed an uncountable number of lives.
"I believe my ancestor HH Holmes and Jack the Ripper are the same man."
Retired lawyer Jeff has spent years speaking to historians and experts, admitting his hypothesis is now an "obsession".
Twenty years ago, one of Jeff's relations told him he was related to sick Holmes, who terrorised Chicago during the 1893 World's Fair.
Holmes was born Herman Webster Mudgett, but changed his name in homage to the fictional detective Sherlock Holmes.
Jeff said: "Imagine knowing you’re related to somebody who murdered dozens, maybe hundreds of innocent people.
"Uncovering this dark family secret drove me to find out more about the man.
"I believe my relation assumed the identity of Jack the Ripper and pulled off one of the greatest cons of all time."
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For a documentary series, showing on channel Blaze from today, Jeff teamed up with ex-CIA agent Amaryllis Fox to solve one of the world’s most famous cold cases.
They met experts from the UK and US, used modern technology and even exhumed Holmes’ body to try and discover who Jack the Ripper was once and for all.
The monster murdered at least five women in the East London areas of Whitechapel and Spitalfields in 1888.
The victims had been mutilated, with cuts to their throats and their abdomens slashed open by a jagged wound, hence the killer’s Ripper nickname.
The identity of Jack the Ripper has never been discovered, but there have been several theories, including that he was East End butcher Joseph Levy, Queen Victoria’s grandson Prince Albert Victor – who had suffered syphilis-induced psychosis that had led him to kill the five women – and even a woman who may have worked as a midwife.
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Jeff's theory is controversial – his relative was a secretive killer, building his "murder castle", The World's Fair Hotel, so that he could slaughter his victims behind closed doors.
His building was designed for his grisly crimes, with airtight rooms connected to pipelines filled with gas, torture rooms, chutes that would drop straight down to the basement where Holmes had acid vats and a crematorium to dispose of his victims' bodies.
He also had surgical tables and an array of medical tools, which he used to dissect some of the bodies to sell their organs and bones on the black market.
Holmes was also a thief and conman, and is thought to have been motivated to kill in order to rob the people staying at his hotel.
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By contrast, Jack the Ripper left his victims out in the open for the police to easily find and targeted impoverished women.
Jeff’s detective partner Amaryllis spent her career tracking down criminals, and has uncovered the identities of terrorist cell leaders and the heads of Russian crime syndicates using forensic science.
And while she was initially sceptical of Jeff's theory because of the differences in their killing styles, there is one find in particular that changes her mind.
Towards the end of tonight's episode, viewers will see Jeff and Amaryllis visit an archive in Chicago, where they discover the first record of Holmes in Chicago – his mortgage deeds for the horror hotel.
There are several more monthly records for him, which document his various financial scams and place him in the US city.
But there is a shock in store – there’s no document in the Chicago records for Holmes between July 1888 and 1889.
His location then is unknown, but Amaryllis says it’s "circumstantial evidence that could place him in London at the time".
It is also believed that an American was taken in for questioning over the Ripper murders, but was later released, and ship logs show there was a man by the name of H Holmes travelling back to the US soon after the London killings ended.
Although circumstantial evidence could indicate Holmes may have been in Whitechapel during the time of Jack the Ripper, there still remains a lack of concrete proof that he was the infamous killer.
Holmes' reign of terror ended when he was arrested in 1894 after stealing a horse.
He was executed for the murder of his business partner Benjamin Pitezel, although he confessed to 27 more killings while on death row.
And while his ancestor remains determined to prove his theory, the mystery of who Jack the Ripper really was continues.
● American Ripper In London is showing on Saturdays from tonight on Blaze at 9pm.
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