Mr Tsvangirai’s illness, revealed in 2016, has divided his Movement for Democratic Change (MDC) party, with three deputy leaders and other officials publicly manoeuvring to succeed the former trade union leader.
The party will have to choose a new leader and launch a campaign against a resurgent Zanu-PF, the ruling party, to contest polls that may be held as early as May.
At the peak of his career, the self-taught son of a bricklayer served as prime minister to Mr Mugabe’s president in a 2009-2013 unity government cobbled together after a disputed and violent election in which scores of his supporters were killed.
His presence helped stabilise an economy in freefall but Mr Mugabe went back on promises to overhaul the country’s partisan security forces and Mr Tsvangirai was pushed back into his familiar role in opposition.
Despite their rivalry, 93-year-old Mr Mugabe harboured grudging respect for an opponent who suffered multiple abuses at the hands of security forces, including a police beating in 2007 that left him with deep gashes in his head.
During their time in power together, the two men developed an uneasy working relationship, squabbling frequently but also taking afternoon tea every Monday and even joking about their frequent head-butting.
In the coalition’s early days, Mr Tsvangirai even said he found Mugabe to be “very accommodative, very charming”.