Mumbai Indians will start their campaign to become the first side to win three straight Indian Premier League titles in an empty stadium in Chennai on Friday, as the pandemic casts a dark shadow over the tournament.
Their opponents Royal Challengers Bangalore have two of the four players in the league who have tested positive in the secure team bio-bubbles, and many have highlighted the stresses of moving into a new eight-week lockdown.
With cases surging in India again, Bangalore's Devdutt Padikkal and Daniel Sams, Delhi Capitals spin star Axar Patel, and Nitish Rana of Kolkata Knight Riders have all been isolated after catching the virus.
Ten ground staff at Mumbai's Wankhede Stadium have also tested positive.
All eight teams are in strict bio-bubbles for the tournament, which concludes on May 30. They include the world's top cricket stars, including England's Ben Stokes and Steve Smith of Australia.
The Board of Control for Cricket in India (BCCI) has appointed bubble integrity managers to police each team.
India captain Virat Kohli spoke about the stress of "bubble life" after India's series against England when he said players were becoming "cooked".
"Scheduling needs to be looked at in future, because playing in 'bubbles' for so long, two to three months, is going to be very, very difficult going forward," Kohli said.
Sourav Ganguly, president of the BCCI, who has controversially commented that Indian players cope better with pandemic stress than foreign stars, said he expected the disruption to ease once the tournament starts.
"Once you are in a bubble nothing happens," he said.
Cases were also found when the IPL was held in the United Arab Emirates last year, "but once the tournament started everything was fine," Ganguly was quoted as saying by the Indian media.
Chennai Super Kings chief executive Kasi Viswanathan told AFP he had no worries about the tournament, which is to be held in six stadiums with no fans.
"The integrity managers are there and we have no fears at all," Viswanathan told AFP.
Overseas players including England batsman Jonny Bairstow believe the IPL will serve as good preparation for the T20 World Cup, which will be held in India in October and November.
"It will be a great opportunity to play at different grounds that we could potentially be playing in for the T20 World Cup," Bairstow, who plays for Sunrisers Hyderabad, said.
South Africa's Chris Morris heads into the tournament as the most expensive player ever after he was bought by Rajasthan Royals for $2.25 million. Morris, who last played an international for South Africa in 2019, said the attention on the World Cup would help him.
"Other guys will hopefully be focusing on the World Cup and that takes their focus away from the IPL and we can jump onto that," said Morris.
"Personally, I'm not worried about the World Cup, I'm here to do the job to win matches and hopefully push for winning the trophy in the IPL."
The IPL has withstood numerous controversies, including corruption, to emerge as the number one T20 league in 2008. A spot-fixing scandal in 2013 led to Chennai and the Royals being suspended for two seasons.