Mr Karamanlis said he had confidence in voters' "maturity"
The people of Greece are voting in a snap general election that is likely to see the governing Conservatives lose their grip on power.
Opinion polls put the opposition Socialists led by George Papandreou ahead of Prime Minister Costas Karamanlis' New Democracy party.
Mr Karamanlis was only half way into his four-year term when he called the election in early September.
He said he wanted a new mandate to tackle Greece's economic problems.
However, the government has been hit by a series of corruption scandals and Mr Karamanlis' opponents say he has failed to fulfil promises to clean up public office and to modernise the country.
As he cast his ballot in the northern city of Thessaloniki, Mr Karamanlis said Greeks were voting to "make a responsible decision for a safe exit from the crisis", the Associated Press news agency reported.
He said the policies he was offering would ensure a "dynamic return to growth from 2011 onwards".
Mr Papandreou, of the Panhellenic Socialist Movement (Pasok), is promising to build a green economy and bring in foreign experts to help Greece overcome its problems.
As he voted in northern Athens, he told supporters he was bringing Greece "a message of hope for change, for a more just society".
The BBC's Malcolm Brabant in Athens says the election campaign has been lacklustre by Greek standards. According to a recent poll, nine out of 10 Greek voters no longer trust the parties, he says.
Mr Papandreou is promising to build a green economy in Greece
Greece has also been dogged by social unrest since police shot a teenager dead last December, sparking the country's worst riots in decades.
On Saturday, a leftist group calling itself The Fire Conspiracy Cells claimed responsibility for a small bomb which exploded near Mr Karamanlis' last election rally on Friday. There were no injuries and only minor damage.
Mr Papandreou needs at least 43% of the national vote to be sure of an overall majority in the 300-seat parliament.
Forty seats are automatically awarded to the leading party and the remaining 260 are divided by proportional representation.
If no party wins outright, President Karolos Papoulias will ask the leader of the largest party to try to form a coalition government.
If that fails, new elections will be called.