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Since 2020, NJPW has unable to run events with a full arena capacity due to COVID-19 restrictions. On January 22, NJPW announced Sakura Genesis for April 4, 2021, making it the first time the event will held since 2018 due to the G1 Supercard taking place instead in 2019 and the 2020 event being cancelled due the COVID-19 pandemic.
On March 1, NJPW announced that the IWGP Heavyweight and IWGP Intercontinental Championships would be unified to create the new IWGP World Heavyweight Championship with the inaugural champion being decided at 49th Anniversary Show, following the IWGP Heavyweight and IWGP Intercontinental Champion Kota Ibushi defending the titles for the final time against El Desperado in the main event. At the anniversary event Ibushi defeated El Desperado to become the inaugural champion. Ibushi will make his first title defense of the IWGP World Heavyweight Championship at Sakura Genesis against the New Japan Cup winner. On March 21, Will Ospreay defeated Shingo Takagi in the New Japan Cup final to face Ibushi at Sakura Genesis.