Slobodan Praljak, 72, died in hospital, according to Croatia's state-run news agency HINA after he drank from a brown bottle at the hearing at the International Criminal Tribunal for the former Yugoslavia (ICTY) in The Hague.
After the judges upheld a 20-year jail term originally imposed in 2013, Praljak, 72, a former military commander of a breakaway Bosnian Croat statelet, shouted out angrily: "Praljak is not a criminal. I reject your verdict."
He then raised a small brown bottle to his lips, and tipped it into his mouth in full view of the cameras filming the appeal hearing for the six Bosnian Croat political and military leaders.
The hearing was then quickly suspended as Praljak's lawyer shouted out: "My client says he has taken poison."
Resuming a few hours later amid confusion, presiding judge Carmel Agius revealed Dutch authorities had already launched an investigation into the incident.
"Courtroom one is now a crime scene," Agius said, but giving no details on what had happened to Praljak except to say he was not in court.
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Court officials also told AFP they had "no comment" on what had happened.
Earlier, AFP journalists had seen an ambulance arrive outside the tribunal in The Hague, and several emergency rescue workers rushed into the building carrying backpacks.
In the complex ruling the judges upheld the jail terms against all six defendants, including a 25-year sentence imposed on Jadranko Prlic, the former prime minister of the breakaway Bosnian Croat statelet, known as Herzog-Bosna.
Praljak was specifically charged with ordering the destruction of Mostar's 16th-century bridge in November 1993, which judges in the first trial had said "caused disproportionate damage to the Muslim civilian population".
A symbol of Bosnia's devastation in the war, the Ottoman-era bridge was later rebuilt.
But in their ruling, the judges in fact allowed part of Praljak's appeal, saying the bridge had been a legitimate military target during the conflict. They also had overturned some of his convictions, but refused to reduce his overall sentence.
The bloody 1992-1995 war in Bosnia, in which 100,000 people died and 2.2 million were displaced, mainly pitted Bosnian Muslims against Bosnian Serbs, but also saw some brutal fighting between Bosnian Muslims and Bosnian Croats after an initial alliance fell apart.
The appeal judges said all six men, who had been found guilty of taking part in a scheme to remove Bosnian Muslims, "remained convicted of numerous and very serious crimes."
In statements sure to anger Zagreb, the judges also upheld the original finding that they had been part of a joint criminal enterprise whose "ultimate purpose was shared" by late Croatian president Franjo Tudjman, and other leaders.
The aim of the scheme was to set up "a Croatian entity that reconstituted area borders and that facilitated the reunification of the Croatian people."
Following the verdict, Croatian President Kolinda Grabar-Kotarovic interrupted an official visit to Iceland to return for talks.
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A 20-year term was upheld against former military leader Milivoj Petkovic, 68, while a 16-year sentence was confirmed against ex-military police chief Valentin Coric, 61, and and 10 years for former police official Berislav Pusic, 65.
Wednesday's verdict comes a week after the judges imposed a life sentence on former Bosnian Serb military commander Ratko Mladic, whose ruthlessness in the conflict earned him the title the "Butcher of Bosnia".
His judgement had also descended into confusion when he accused the judges of lying and had to be dragged away into a nearby room to watch the end of the proceedings.
The ICTY charged Prlic and his co-defendants in 2004. The six surrendered with Croatia under pressure to comply with the court in return for joining the European Union.
The ICTY closes its doors on December 31, having indicted and dealt with 161 people.
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