The 64-year-old wartime leader was in confident mood as he made his opening statement from the dock in the courtroom in the Hague.
Karadzic said he would use his trial "to defend the greatness" of the Serb nation, and its role in the Bosnian war.
"I stand here before you not to defend the mere mortal that I am, but to defend the greatness of a small nation in Bosnia Herzegovina, which for 500 years has had to suffer and has demonstrated a great deal of modesty and perserverance to survive in freedom," he told the court.
"I will defend that nation of ours and their cause that is just and holy."
Karadzic stands charged as the "supreme commander" of an ethnic cleansing campaign of Croats and Muslims in which 100,000 people were killed and 2.2 million displaced between 1992 and 1995.
He has pleaded not guilty and denies there was any intention to expel Muslims and Croats from the Serbian republic.
He presented a range of videos and documents to the court and read what he called evidence of his contentions from a computer screen on the desk before him in the dock.
"We have a good case," Karadzic said. "We have good evidence and proof."
Karadzic had refused to attend the opening of his trial last October, insisting he needed more time to prepare his case, causing a four-month delay.
He had sought a further postponement of proceedings until 17 June after his opening statement concludes on Tuesday, apparently to study additional prosecutive evidence.
The request was denied by the court, which ruled that the first prosecution witness will testify on Wednesday.
Karadzic was arrested in July 2008 after 13 years on the run.
If found guilty, he faces life imprisonment.