In one of the last remaining cases from the break-up of Yugoslavia, UN judges in The Hague will rule on his appeal against his 2016 conviction for genocide and war crimes, and his 40-year sentence.
Once the most powerful Bosnian Serb political figure, Karadzic, now 73, was notorious for his role in the 1995 Srebrenica massacre, the worst bloodletting on European soil since World War II.
Around 100,000 people eventually died and 2.2 million others were left homeless in the brutal three-year war that pitted Muslims, Serbs and Croats against each other.
"I think this verdict is historical for justice," Munira Subasic of the Mothers of Srebrenica victims' association told AFP, adding that they wanted Karadzic to get a full life sentence.
"If Karadzic does not get what he deserves it means that there is no justice in this world and that it is possible to commit crimes without risking penalties."
The ruling is due to start at 1300 GMT at the International Residual Mechanism for Criminal Tribunals, which deals with cases left over from now-defunct courts for the former Yugoslavia and Rwanda.
Karadzic's case still bitterly divides the country he helped drive to war, with widows of Srebrenica hoping he dies in prison even as Bosnian Serbs have honoured him with a university dorm in his name.
But it also comes at a crucial time for international courts as they come under attack from quarters including the administration of US President Donald Trump, and reel after a series of mistrials.
Karadzic's lawyer Peter Robinson said his client "fervently believed that the Trial Chamber judgment was wrong and the product of an unfair trial".
"He (Karadzic) is an optimistic person by nature," Robinson said.
In 2016, Karadzic was found guilty on 10 counts including orchestrating a nearly four-year siege of the Bosnian capital Sarajevo, where more than 10,000 people died in a campaign of sniping and shelling, according to prosecutors.
He was also found guilty of genocide in Srebrenica, where Bosnian Serb troops slaughtered more than 8,000 Muslim men and boys in the eastern Bosnian enclave, which was supposed to be under UN protection, and buried their bodies in mass graves.
A poet and psychiatrist turned ruthless political leader, Karadzic has appealed the sentence on 50 grounds and accused judges of conducting a "political trial" against him.
He represented himself at his trial, but has Robinson assisting him.
Prosecutors, however, said Karadzic and others including his military alter-ego, former Bosnian Serb army commander Ratko Mladic, wanted to "permanently remove Muslims and Croats" from territory claimed by Bosnian Serbs at the time.
United Nations prosecutors also asked judges to reverse his acquittal on a second charge of genocide in Bosnia's municipalities and hand him a life sentence.
Mladic, 76, dubbed the "Butcher of Bosnia", is currently appealing a life sentence on similar charges. He has previously refused to testify at Karadzic's trial, calling the UN tribunal "satanic".
Former Serbian president Slobodan Milosevic, Karadzic's long-time patron during the war, was on trial at the ICTY until his death in 2006.