Gaines, who oversaw a tripling in the share price of the world's fourth-biggest iron ore miner in the last four years, will remain on Fortescue's board as a non-executive director and assist in the search for the new CEO.
The move comes as Fortescue's chairman and Australia's richest man, Andrew Forrest, pushes to turn the company into the world's biggest green energy group, with a focus on hydrogen at its green power arm, Fortescue Future Industries (FFI).
It did not set a timeline for the change over.
Fortescue has begun a worldwide search to identify its next chief executive and other leaders with "global experience across heavy industry, manufacturing, and renewable energy," it said in a statement.
Its shares slipped as much as 1.8% and traded 0.6% lower in a broadly weaker market by 1249 GMT, as investors mulled how the transition would fit into the company's strategy.
"Management churn at Fortescue has been an ongoing concern in the market, including risk to CEO tenure in the wake of Elizabeth Gaines selling the majority of her Fortescue shares in September," Credit Suisse analyst Saul Kavonic said.
Fortescue lost its chief operating officer Greg Lilleyman, a highly respected executive in the iron ore industry, and two other senior leaders following a review earlier this year of cost blowouts at its Iron Bridge magnetite project.
Kavonic had flagged the risk of Gaines potentially quitting in a September note after she sold around 65% of her shares, excluding performance rights.
Analysts also pointed to some disenchantment at Fortescue after long-term incentives were cut.
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