Microsoft said Zain Nadella, son of chief executive Satya, died on Monday morning.
He was 26 years old and had been born with cerebral palsy.
The software maker told its executive staff in an email that Zain had died. The message asked executives to hold the family in their thoughts and prayers while giving them space to grieve privately.
Since succeeding Steve Ballmer as chief executive in 2014, Mr Nadella has focused the company on designing products to better serve users with disabilities and cited lessons he learnt raising and supporting Zain. He joined the software company in 1992.
Mr Nadella was born in Hyderabad, India, and received his bachelor's degree in electrical engineering at Mangalore University.
He serves on the board of trustees at Fred Hutchinson Cancer Research Centre in Seattle, Washington.
Last year, the Children’s Hospital, where Zain received much of his treatment, joined with Mr Nadella and his wife Anu to establish the Zain Nadella Endowed Chair in Paediatric Neurosciences, as part of Seattle Children’s Centre for Integrative Brain Research.