Mr Karadzic is one of a trio of Serb leaders brought to trial in The Hague for war crimes during the violent break-up of multi-ethnic Yugoslavia between 1991 and 1999.
The 67-year-old began his own defence against charges of genocide, war crimes and crimes against humanity, and will cross-examine witnesses himself.
Reading from a written speech, he said Muslims had faked the circumstances of two shellings of a marketplace in the Bosnian capital Sarajevo during a siege by Serb forces.
More than 100 people were killed in the attacks.
"Sarajevo is my city, and any story that we would shell Sarajevo without any reason is untrue," he said, reiterating long-standing allegations by the Serb side.
These allegations have already been refuted by the Hague tribunal in an earlier case.
Prosecutors at the International Tribunal for the Former Yugoslavia say Mr Karadzic was jointly responsible for the shelling of Sarajevo when Bosnian Serb forces besieged it from 1992-6.
He is also charged with being behind the massacre of 8,000 Bosnian Muslims in Srebrenica in 1995.
"Instead of being accused, I should have been rewarded for all the good things I have done. I did everything in human power to avoid the war. I succeeded in reducing the suffering of all civilians," he told the court at the start of his defence.
"I proclaimed numerous unilateral ceasefires and military containment. And I stopped our army many times when they were close to victory."
Leaning forward in his chair, he emphasised points with jabs of his right hand and paused occasionally to adjust his glasses.
He said the first marketplace shelling, in February 1994, in which 68 people were killed and 144 were injured, had been orchestrated, as was a second a few days later.
During the trial of Bosnian Serb General Stanislav Galic, the tribunal established that Bosnian Serb forces were responsible for shelling the market place.
Mr Karadzic was arrested in 2008 in Belgrade, where he had been living in disguise as a new age health guru.
The trained psychiatrist worked for a private clinic, posing as a specialist in alternative medicine under the assumed name of Dragan Dabic.
Bosnian Serb military leader Ratko Mladic eventually went on trial in The Hague this year, after 16 years on the run until his capture in a cousin's farmhouse in Serbia in May 2011.
But former Yugoslav and Serbian president Slobodan Milosevic died in 2006 before the end of his trial.
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