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The Guangzhou maritime affairs bureau said the collision sent five vehicles, including a motorbike, tumbling off the bridge and either into the water or onto the ship below.
The container vessel was travelling between the cities of Foshan and Guangzhou when it rammed the Lixinsha Bridge at around 5:30 a.m. (2130 GMT), state broadcaster CCTV said.
The boat "came into contact with... the bridge pillars, causing the roadway above to collapse," CCTV reported.
As of 10 a.m., "two people have been rescued, two have died, one crew member has been lightly injured, and three people remain missing," the Guangzhou bureau said in an online statement.
Footage broadcast by CCTV showed rescue personnel in orange jumpsuits racing in dinghies across a murky waterway towards a high bridge with a yawning gap in its middle.
Other patrol boats flashed their lights as they circled the area where the collapse took place, though the cargo ship appeared to have been towed away.
Photos published by CCTV earlier on Friday showed the red and white vessel lodged at a diagonal angle between two of the bridge's pillars as water cascaded out of severed pipes onto its deck, where some debris was visible.
The maritime bureau said the cause of the incident was "under investigation, and rescue work is proceeding at full strength and in good order".
CCTV reported that dozens of rescuers had been dispatched to the scene, including reinforcements from the nearby tech hub of Shenzhen.
The ship's owner has been brought under "control", the broadcaster said.
The region where the collision took place is a major industrial and manufacturing area crisscrossed by a dense network of shipping routes.
Similar accidents have occurred in China before, including in 2012 when a newly built cruise liner bumped into a bridge in the eastern city of Wenzhou, causing no casualties.
In 2007, nine people were killed when a cargo vessel struck a 1,600-meter-long bridge in southern Guangdong province, causing a section of it to collapse.
