His brother Charles, 82, has appeared in recent months to pick up some of the slack left over by his brother's illness.
David, who was diagnosed with prostate cancer nearly two decades ago, is the executive vice president at Koch Industries.
Koch is leaving for health reasons, according to an internal Koch Industries memo obtained byCNBC The 78-year-old business tycoon was diagnosed with prostate cancer more than two decades ago and his health has been deteriorating. He has focused many of his philanthropic efforts on finding a cure for prostate cancer, including with contributions of almost $600 million to medical research and institutions.
The 78-year-old NY resident is suffering from deteriorating health, according to a letter from older brother Charles Koch sent to company officials Tuesday. And in a sign about its shifting strategy, it appears to be more willing to take on the Trump administration than many other political organizations on the right.
Charles Koch wrote: "We are deeply saddened by this, as we miss David's insightful questions and his many contributions to Koch Industries". That group, the network's primary political vehicle, has been one of the most active television advertisers so far in this year's midterm congressional campaign.
The clothing-to-chemicals conglomerate is the second-largest privately held company in the United States with annual revenues of more than $115 billion from interests in energy, chemicals and other sectors.
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And last week, Americans for Prosperity unveiled a digital ad buy in North Dakota to thank a Democrat, Sen. That includes $100 million to the New York State Theater at Lincoln Center, now the David H. Koch Theater, and $65 million for renovations at the Metropolitan Museum of Art.
David was the Libertarian Party's vice presidential candidate for the 1980 presidential election. His ticket, with Ed Clark, received just 1 percent of the popular vote.
The billionaire Koch brothers are taking on US President Donald Trump by launching a multi-million dollar campaign in support of free trade.
Mark Holden, who has spent a career at Koch Industries and now helps run their political efforts, said the Koch network would continue to expand even as one of its founders steps aside.
Although David Koch's involvement had been reduced in recent years, he still held several top positions within the Koch network, including as chairman of a foundation that supports Americans for Prosperity.
While Charles Koch has remained in the family's hometown of Wichita, David Koch is a prominent figure in NY, where he has been a big contributor to Memorial Sloan Kettering Cancer Center and a leading arts patron.