Pope John Paul II waved to pilgrims after appearing at the window of his hospital room where he is recovering from flu and breathing difficulties.
It is not known how much longer the Pope will stay in hospital
He sounded hoarse as he gave the short final lines of the Angelus blessing.
It was his first public appearance since he was rushed to Rome's Gemelli hospital on Tuesday.
Crowds had massed for a glimpse of the 84-year-old pontiff and clapped after his appearance. Many others watched on large screens in St Peter's Square.
The blessing, which consists of just a few lines in Latin, was broadcast via radio link from the 10th floor of the Gemelli hospital at noon (1100 GMT).
Shortly beforehand, the white curtains of the hospital room were drawn back and the Pope appeared at the window wearing his traditional white cassock and skullcap.
11th Century origins
Pope delivers it weekly
Triple repetition of Hail Mary
Interspersed with responses from the faithful
He managed to wave to pilgrims who had gathered in the car park below and give the sign of the cross at the end of the blessing.
In a message read out on his behalf by an aide, he gave thanks for the prayers and support of pilgrims around the world and said he would continue to lead the Catholic Church as long as he was able.
"Even from here in the hospital, among other sick people to whom go my sincere best wishes, I continue to serve the Church and all humanity," he said.
The BBC's David Willey in Rome said the Pope sounded hoarse as he gave the short blessing, and became almost inaudible, although there were technical problems.
It is clear his illness over the last week has made speech even more difficult for the Pope, says our correspondent.
The pontiff's speech had already grown slurred and often incomprehensible in recent months as a result of the progress of Parkinson's disease.
He is believed to have suffered a laryngo-spasm last week, a closure of the larynx that blocks the passage of air to the lungs.
There had been concerns that he could develop pneumonia.
But his heart and lungs are said to be performing normally, and the Vatican has been keen to stress that this is not a life-threatening illness.
On Saturday, Italian bishop Vincenzo Paglia said the pontiff was "getting better and he's happy" after delivering a message of good wishes with three other bishops.
The prelate had also attended a gathering of some 100 bishops of various Christian denominations who held an ecumenical prayer service in the hospital chapel for the ailing leader of the Roman Catholic Church.
No further medical updates are expected until Monday.
It remains unclear how much longer the Pope will remain in hospital.
For the first time in his long reign, the Pope will miss the Ash Wednesday prayer service in St Peter's this week, marking the start of Lent.