The Pope made his appeal today before praying the midday Angelus with the crowds gathered in St. Peter's Square.
He addressed the tens of thousands of people from the window of his study, on a day when the temperature reached 35 C (95 F) in the shade.
The Holy Father said he hoped that everyone will "be able to live serenely a few days of merited rest and relaxation."
At the same time, he appealed for prudence on the part of "those who set out for different holiday places."
"Every day, unfortunately, especially on weekends, incidents occur on the roads with so many human lives tragically cut short, and more than half of the victims are young people," Benedict XVI said.
Although in "recent years much has been done to prevent such tragic events, … there can be and must be more done with the contribution and commitment of all," added the Pontiff. "Distraction and superficiality must be combated, which in an instant can ruin one's own future and that of others.
"Life is precious and unique: It must always be respected and protected, including with correct and prudent conduct on the roads."
Before concluding, the Holy Father entrusted "those who are traveling" to the Blessed Virgin Mary, and implored divine mercy "for road victims."
After praying the Angelus, the Pope greeted pilgrims in French, English, Spanish, German and Italian, to wish them all happy holidays.
Benedict XVI is schedule to begin his vacation July 11 in the Val d'Aosta in the Italian Alps; it will end on July 28.
He will then travel to Castel Gandolfo, the papal summer residence, south of Rome, to continue his ordinary activities.