Emergency services were scrambled to the Enyobeni Tavern, in the Scenery Park township, early on Sunday morning and found a number of bodies, with several others reportedly injured.
Relatives have not yet been given permission to see the bodies, say local reports, and have been calling out the names of dead loved ones.
After initial conflicting reports about death toll, health officials have confirmed they believe at least 22 people have died.
The cause of the tragedy is not yet known but there are reports it could be due to a poisonous substance such as a gas leak or a possible stampede at the tavern.
South African news service Daily Dispatch said that the bodies were laying in the venue on chairs with ‘no obvious sign of injury’.
South African Police Service SAPS has launched an investigation into the incident and claimed they did not wish to speculate until their enquiries were complete.
Brigadier Tembinkosi Kinana told Newsroom Afrika: “The SAPS confirms an incident where people were found dead in a tavern in Scenery Park in the area of East London.
“We received this report in the early hours of Sunday. The circumstances surrounding the incident are under investigation as we speak.
“We do not want to make any speculation at this stage, our investigation is continuing.”
Brigadier Kinana added that it was too early to determine the cause of death of the young adults aged between 18 and 20.
Eastern Cape Police Commissioner Nomthetheleli Lilian Mene told SABC there was an “alleged stampede” inside the tavern.
Siyanda Manana, a spokesperson for the Eastern Cape provincial health department, said the bodies will be transported to state mortuaries where relatives are expected to help identify both male and female victims, said
“We are going to immediately be embarking on autopsies so we can know the probable cause of death,” he told Reuters as forensic personnel continued their work at the cordoned-off crime site at Enyobeni Tavern.
“We are talking 22 bodies right now,” Manana added.
Additional reporting by agencies