A total of 49 patients have absconded from Jose Pearson hospital near Port Elizabeth this week, officials said.
Although 26 have since returned to the wards, police are now primed to join door-to-door searches for the rest.
The patients, some of whom have been in hospital for 18 months, were said to want to spend Christmas with family.
But health officials said the patients posed a risk to public health and needed to return to hospital immediately.
"I think that those who returned are aware that they are putting themselves and their families at risk," hospital spokesman Siyanda Manana told the South African Press Association.
"If they [the others] do not return immediately, department officials will be accompanied by members of the South African Police Service in a door-to-door search."
Widespread - Experts think South Africa has underestimated the spread of TBCorrespondents say South Africa is battling the spread of virulent forms of TB which are especially dangerous for those infected with HIV, the virus which can lead to Aids.
The country has an estimated 5.4 million people living with HIV.
Just 400 people have been officially diagnosed with extremely drug-resistant TB, or XDR-TB, the Associated Press reports.
But the true figure is thought to be considerably higher because many people die before being diagnosed.
Several provinces in South Africa have been forced to take legal action to force drug-resistant TB patients to stay in hospital, AP adds. - BBC - SABC
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