The incident happened in Ab Band district of Ghazni province, on the highway from Kabul to Kandahar, the capital of the south and Afghanistan's second largest city, on what is one of the most dangerous roads in the country.
One official said the fuel tanker belonged to an Afghan trader and Ghazni is part of the supply route for NATO goods coming into Afghanistan from the north and heading south.
"At around 6:30 am (0200 GMT) a passenger bus collided with a fuel tanker in the Spin Band area of Ab Band," Mohammad Ali Ahmadi, the deputy governor of the province, told AFP.
"As a result, the fuel tanker and the passenger bus caught fire and 51 people were killed and six others were wounded in the collision. There are women and children among the victims," he said.
He said most of the dead were burnt beyond recognition. Four women were among the 50 killed on the bus and the driver of the fuel tanker was also killed, he said.
Interior ministry spokesman Sediq Sediqqi said 50 people had died.
Baz Mohammad Himmat, the head of the main hospital in Ghazni city, said only that five wounded had been brought in after the accident, but had no information about the dead.
Sardar, an 18-year-old survivor with head injuries, told AFP what happened.
"I was sitting in the back row and the driver was driving very fast when it crashed with the tanker. The bus caught fire, the passengers were screaming," he said in hospital.
"I managed to throw myself out of the bus because I was sitting in the last row. I saw people burning, it was terrible," he added.
High-casualty road accidents are common in Afghanistan, where roads are perilous and many vehicles are old.
Officials said there was no immediate suggestion that insurgents had been involved in Friday's accident, although Ghazni is a flashpoint for Taliban attacks.
"I believe reckless driving and the narrow road are to be blamed for this tragic accident," said Ghazni police chief Zerawer Zahid.
The Taliban is leading a 10-year insurgency against the US-backed government and 117,000 NATO troops who by the end of 2014 are due to withdraw and hand over security responsibility to Afghans.
In Ghazni on Thursday, a military spokesman said an insurgent attack killed a NATO soldier.
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