A third of senior management jobs will be axed at the John Lewis Partnership as the company streamlines its structure from February next year.
The partnership is merging the managements of its High Street department stores and Waitrose grocery chain into a single team.
John Lewis has been struggling in a tough retail climate.
The restructuring aims to save £100m, through the loss of about 75 of its current 225 senior head office roles.
One of the senior partners who will depart is Rob Collins, managing director of Waitrose, who has been with the business for 26 years. He said there was not a role in the new structure that he believed would be right for him.
John Lewis chairman Sir Charlie Mayfield said: "These changes will be difficult for some of our Partners and we will implement as carefully and sensitively as we can."
Employees at John Lewis, including both management and shop floor staff, are known as "partners" due to the company's co-ownership model.
There would be "little or no disruption" for customers, he said, but the restructuring would create a more unified leadership team and cost structure.
Last month, the retailer reported a half-year loss for the first time in its history amidst a difficult UK retail environment.
"The lesson of the last two years is that we need more innovation, faster decision-making and bolder steps to align our operating model with our strategy," the chairman said.
The company said of the customers that accounted for its greatest sales, the majority shopped at both its department stores and at Waitrose.
Retail analyst Richard Lim said it was a "bold" move which should deliver cost-saving efficiencies.
"Against a backdrop of rising costs and fiercer competition, a new leaner and flexible operating model will help restore profitability during a period of rapid change within the sector," he said.
However, Thomas Brereton, retail analyst at GlobalData, warned the changes would have to be implemented carefully to avoid disruption.
"The long-term impact of running a unified strategy for two retailers with such a varied proposition is questionable," he said.