Plavsic was born in Visoko, northwest of Sarajevo in the Yugoslav republic of Bosnia and Herzegovina, in 1930. She studied in New York for two years in the 1970s as a Fulbright scholar and later became a biology professor at Sarajevo University, with a specialty in plant diseases. She rose to the position of dean of the biology department. Her professional rise was checked when she was passed over for membership in Yugoslavia's Academy for Arts and Sciences in the late 1980s.

Plavsic became active in the nationalistic Serbian Democratic Party of Bosnia and Herzegovina (SDS), founded in the summer of 1990. From 1990 until 1992 she was one of the two Serbs elected to Bosnia's collective presidency.

With the outbreak of war, Plavsic left the Bosnian collective presidency in April 1992 to join other leaders of the newly declared Serbian Republic of Bosnia at Pale, outside Sarajevo. Karadzic was president, and Plavsic was one of two vice-presidents.

Plavsic justified the killing of Muslims and Croats by Bosnian Serbs as a natural biological phenomenon. She explained the crowding of Muslims into ethnic ghettos as a normal Muslim way of life. She shocked even Serbian nationalists with her composure at seeing Serbs die for the goal of an independent Serb state, and television cameras showed her embracing a Serb warlord as a hero after his bloody capture of a contested town.

The peace agreement reached at Dayton, Ohio, in 1995 barred indicted war criminals from political office. Karadzic, who was indicted, resigned in July 1996 but continued to give orders through Plavsic, his figurehead successor. Elections on Sept. 14, 1996, returned Plavsic to office as president of the Serb republic. Her home, office, and political base were in the city of Banja Luka in the northwestern part of the state.

After taking office she learned that corruption by Karadzic and his associates, who controlled much of the Serb republic's commerce, was having a serious adverse effect on the economy. In addition, the state's failure to implement parts of the Dayton peace accords kept it from receiving foreign aid. Under international pressure, Plavsic fired several government officials and promised political reforms. Karadzic in turn barred her from SDS party meetings and bugged her office.

The conflict reached a crisis in the summer of 1997. In July Plavsic dismissed her interior minister, dissolved the parliament, and called for a general election. The parliament continued to meet in Pale with the approval of the Karadzic-controlled supreme court. As Plavsic tried to qualify for foreign aid without appearing to be a puppet of foreign powers, further conflicts erupted over control of the police and the media.