Bill and Melinda Gates, two of the richest people in the world, who reshaped philanthropy and public health with the fortune Mr. Gates made as a co-founder of Microsoft, said on Monday that they were divorcing.

For decades, Mr. and Ms. Gates have been powerful forces on the world stage, their vast charitable contributions affording them access to the highest levels of government, business and the nonprofit sector. The Bill and Melinda Gates Foundation, with an endowment of some $50 billion, has had immense influence in fields like global health and early-childhood education, and has made great strides in reducing deaths caused by malaria and other infectious diseases. Over the past year, the couple have been especially visible, regularly commenting on the worldwide fight against Covid-19 as their foundation spent more than $1 billion to combat the pandemic.

“After a great deal of thought and a lot of work on our relationship, we have made the decision to end our marriage,” Mr. and Ms. Gates said in a statement that was posted to Twitter.

They went on to say that they had “built a foundation that works all over the world to enable all people to lead healthy, productive lives” and that they “continue to share a belief in that mission,” but they “no longer believe we can grow together as a couple in this next phase of our lives.”

The foundation said in a statement that Mr. and Ms. Gates would remain co-chairs and trustees and that no changes were expected at the organization.

“They will continue to work together to shape and approve foundation strategies, advocate for the foundation’s issues and set the organization’s overall direction,” the statement said.

Even so, the divorce will create new questions about the fate of the Gates fortune, much of which has not yet been donated to the Gates Foundation. Mr. Gates, 65, who co-founded Microsoft, is one of the richest people in the world, worth an estimated $124 billion, according to Forbes. The Gateses have been married for 27 years and have three children, ages 18 to 25.

“The Gates Foundation is the most important and influential philanthropic entity in the world today,” said Rob Reich, a professor of political science at Stanford University. “The divorce may have huge repercussions for the foundation and for its work across the globe.”

With 1,600 staff members in offices around the world, the Gates Foundation gives away roughly $5 billion each year in areas like global public health and development. Over more than two decades, the foundation has spent billions to push vaccines to the developing world, working with pharmaceutical executives to transform the market.

The foundation tapped its expertise and relationships to play a significant role in formulating the global response to the pandemic, investing early in vaccine candidates and helping shape Covax, the global initiative organizing the purchase of vaccines for 92 poor countries and dozens of other nations.