Serving and former officers, including those in senior positions, could face charges or misconduct proceedings for failings and cover-ups over Britain's worst sporting disaster, the Independent Police Complaints Commission (IPCC) said.
Last month, Prime Minister David Cameron apologized to families of the victims after a damning report detailed a catalogue of errors and evidence that police dishonestly tried to deflect blame on to fans of Liverpool soccer club.
The victims, many young, died in an overcrowded, fenced-in enclosure at the Hillsborough stadium in Sheffield, northern England, at an FA Cup semi-final against Nottingham Forest.
The tragedy changed the face of English soccer and ushered in a new era of modern, all-seated venues.
An independent panel found the police response to the disaster had been flawed and 41 lives could have been saved.
It also concluded that police had sought to blame the Liverpool fans, portraying them as aggressive, drunk and ticketless and bent on packing into the already crowded stadium, vindicating families who fought a 23-year campaign to find the truth.
Senior police edited their officers' witness statements from the day to paint them in a less damaging light, the report said. South Yorkshire Police removed negative comments from 116 out of 164 police statements.
"The report revealed extremely serious and troubling issues for the police," said IPCC deputy chairman Deborah Glass.
"Its contents provoked a demand for those responsible for the actions revealed in the report to be held to account."
She said their probe would "without a shadow of a doubt" be Britain's biggest inquiry into police behavior.
"We do not yet know how many officers or retired officers fall to be investigated. We do not underestimate the size of our task," she added.
The investigation will look at allegations that individuals or institutions were culpable for the deaths, and so should face manslaughter charges, and at claims that evidence was fabricated after the disaster and lies then spread to lawmakers and the media.
One senior officer, Norman Bettison, the chief constable of West Yorkshire Police who has been accused of being part of a cover-up, announced last week he would retire next year to allow a full investigation into charges against him.
Keir Starmer, the Director of Public Prosecutions, said prosecutors would consider all the material now available to see whether there was already evidence to bring criminal charges against any individual or corporate body.