The World Cup kicks off at the height of South Africa's winter, bringing in hundreds of thousands of visitors during peak flu season and raising concerns aboout a resurgence of swine flu.
The H1N1 strain has killed nearly 16,000 people, proving less lethal than regular flu despite the global alarm.
But health minister Aaron Motsoaledi said recently that a possible new swine flu flare-up was one of his "biggest nightmares" about the 2010 showcase to be played as night-time temperatures in several host cities dip toward freezing.
Football body FIFA has advised the tournament's 32 teams to be vaccinated against the H1N1 strain, but has warned against panic.
"We are very carefully monitoring with the WHO and the health authorities in South Africa," Jiri Dvorak, FIFA's chief medical officer told AFP on the sidelines of a recent pre-tournament football medicine conference in the Sun City resort.
"We are really not worried about a special situation. We have to deal with the situation as it comes. Up to now, we have absolutely no indication that we should be worried."
Despite accusations of inflating the swine flu threat, the World Health Organisation (WHO) on Wednesday said it was too early to declare that the pandemic had peaked.
Last year, 12,000 people caught swine flu in South Africa, with nearly 100 fatalities.
South Africa's medical facilities -- which range from first-class private clinics to overstretched state hospitals -- will be beefed up by military health services during the June 11-July 11 tournament.
"Everything that we are doing is geared up to deal with any eventuality," Victor Ramathesele, general medical officer for South Africa's 2010 organising committee, told AFP.
"Everything is in our plans and we are confident that we deal with any public health and emergency medical situations that might arise during the tournament."
Seasonal flu sufferers accounted for 90 percent of cases at clinics set up for players and VIPs at the 2009 curtainraiser Confederations Cup, staged during the midst of the swine flu hype last June.
"If you're going to have a major event like the 2010 FIFA World Cup, it becomes critical that we prepare ourselves adequately both for seasonal flu and H1N1," said Ramathesele.
While several nations have scaled down controls due to waning infections, caseloads have risen in western Africa including Senegal and Mauritiana.
South Africa's private Netcare Travel Clinics has cautioned against complacency ahead of the Cup.
"The H1N1 virus could well make a big return to South Africa during our next flu season," said Pete Vincent.
"We will have a lot of people visiting the country over the period of the World Cup. Therefore, the conditions for a rapid spread of the virus will be good."
The National Institute of Communicable Diseases warns in its World Cup vistors guide that the H1N1 strain is expected to cause the majority of infections in 2010.
"There will be a lot -- we can expect that. You can't contain an outbreak of influenza," said the institute's Lucille Blumberg.
But the majority of cases will be mild, she said, with many northern hemisphere visitors likely to be immune to the strain as many would have been exposed to the virus last year.
"If you look back on it now, it (the 2009 outbreak) wasn't that different to a severe influenza season. I don't think we are going to see huge, huge problems."