Karis, 61, was found unresponsive inside the cell where he was housed alone and later pronounced dead at 6:40 a.m., the state Department of Corrections and Rehabilitation said.
The cause of death is not known, and an autopsy will be performed.
What is known is that he did not die from a state-ordered execution. California has not executed an inmate since January 2006 because of legal fights over the death penalty.
Karis was sent to death row Sept. 20, 1982, after his conviction in the rape and murder of 34-year-old Peggy Pennington. He abducted Pennington and another woman in July 1981 as they took their daily walk around their workplace at the El Dorado County Welfare Department.
He took them at gunpoint to a remote area near Placerville and forced both to remove their clothes.
Karis raped one of them, then let them get dressed, marched them to another spot and shot both of them.
Pennington died, but the other victim, a 27-year-old woman, survived and later testified at trial.
Karis was sent to death row, but a federal judge overturned his sentence in 1998 after finding that evidence of Karis' tormented and abusive childhood had not been presented as evidence during the penalty phase.
Karis faced a second trial in 2007 in Sacramento and refused to allow his lawyers to offer evidence of his childhood abuse or anything else that might win him a life sentence.
He was returned to death row and, until Thursday, was one of 729 inmates awaiting execution.
Karis' public defender in his original trial, Stephen Tapson, recalled his client as a "big, gruff guy."
During the death penalty phase, the judge did not allow the abuse evidence to be used and ordered Karis sent to death row, said Tapson, now one of El Dorado County's most prominent defense attorneys.
Appellate lawyers later returned to court to try to present the childhood abuse evidence, but Karis refused to allow it, taking over the case himself and telling the judge that the evidence didn't "amount to a hill of beans."
"They spent hours digging up all these terrible things about his childhood to present to a jury in hopes they would not send him to death and he basically said '(Screw) you,' " Tapson recalled. "So he chose his own death penalty."
A federal judge in Sacramento overturned the death penalty in 1998 because evidence of his childhood trauma had not been presented, and Karis faced another penalty phase trial in which jurors again concluded he should die.
Tapson said the millions of dollars spent and years of legal wrangling "is a classic example of the need to abolish the death penalty because they just die there, so you don't have to worry about it."
"It's much cheaper if they die in prison rather than trying to kill them," he added.
California voters so far have not agreed with that stance. They rejected a ballot measure in November that would have eliminated the death penalty, and victims' groups have launched efforts to overturn impediments to restarting executions in California, among them an effort to switch to using one drug instead of three to execute inmates.
"It's a shame that a monster like Karis was permitted to die of natural causes," El Dorado County District Attorney Vern Pierson said. "Obstructionist tactics and weak representatives in Sacramento allowed this to happen.
"It's time for the governor to enact real reforms to the death penalty system."