Ratko Mladic, 69, is the last of the main protagonists in the Balkan wars of the 1990s to face an international trial in The Hague.
He is accused of orchestrating the massacre of more than 7,000 Muslim boys and men at Srebrenica in 1995.
Ratko Mladic calls the accusations “monstrous” and the court has entered a “not guilty” plea on his behalf.
He spent 15 years on the run before being apprehended by Serb forces last May and sent to The Hague.
He has been awaiting trial in the same prison as his former political leader Radovan Karadzic, who was arrested in 2008 and is now about half way through his trial on similar charges to General Ratko Mladic.
In the hours leading up to the opening of proceedings, members of the Mothers of Srebrenica group gathered for a vigil outside the court.
Judicial authorities have rejected defense calls to delay proceedings, most recently a petition to have the Dutch presiding Judge Alphons Orie replaced on grounds of alleged bias.
The number of crimes of which Ratko Mladic stands accused has been almost halved to speed up his trial.
Ratko Mladic is accused of committing genocide and other crimes against Bosnian Muslims and Croats in a brutal campaign of ethnic cleansing that began in 1992 and climaxed in Srebrenica in 1995.
Then, Serb fighters overran the Srebrenica enclave in eastern Bosnia – supposedly under the protection of Dutch UN peacekeepers. Men and boys were separated off, shot dead and bulldozed into mass graves – later to be dug up and reburied in more remote spots.
Ratko Mladic is also charged in connection with the 44-month siege of Sarajevo during which more than 10,000 people died.
These were the worst atrocities in Europe since the end of World War II.
Over 200 hours, the prosecution will make its case against General Ratko Mladic, taking testimony from more than 400 witnesses.
Pre-trial hearings have been characterized by ill-tempered outbursts from Ratko Mladic, who has heckled the judge and interrupted proceedings.
“The whole world knows who I am,” he said at a hearing last year.
“I am General Ratko Mladic. I defended my people, my country… now I am defending myself.”
The case has stirred up strong emotions among watching survivors, with some shouting “murderer” and “killer” from the court gallery.
Ratko Mladic suffered at least one stroke while in hiding and remains in frail health.
The architect of the Balkan wars, former Serbian President Slobodan Milosevic, died in detention in his cell in 2006, before receiving a verdict.
Ratko Mladic charges
• Counts 1/2: Genocide of Bosniaks and Bosnian Croats in Bosnia-Hercegovina and Srebrenica
• Count 3: Persecutions
• Counts 4/5/6: Extermination and murder
• Counts 7/8: Deportation and inhumane acts
• Counts 9/10: Terror and unlawful attacks
• Count 11: Taking of UN hostages
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