The president of the Howard Hughes Medical Institute in Bethesda has resigned after a board of trustee inquiry into his controversial management practices and spending by him and his wife.

The resignation of Dr. Donald J. Fredrickson, who has guided the wealthy biomedical research organization during a period of dramatic change, was accepted by the trustees on Monday.

Frederickson, a former chief of the National Institutes of Health and one of the country's most prominent scientific administrators, will be succeeded temporarily by Dr. George W. Thorn, chairman of Hughes' board, while the institute searches for a permanent replacement, the institute said yesterday.

Under Fredrickson's direction, the Hughes Institute has undergone its most dramatic changes in its 34-year history. Founded in 1953 by reclusive billionaire Howard R. Hughes and funded with proceeds from its ownership of Hughes Aircraft Corp., the tax-exempt institute for many years quietly established and supported laboratory units at teaching hospitals around the country.

In 1985, however, the institute attracted attention when it auctioned off Hughes Aircraft to General Motors for $5.2 billion, becoming overnight one of the largest private philanthropies in the world and potentially a much more powerful force in biomedical research.

Frederickson's resignation comes a month after the Hughes Institute announced that the trustees were conducting a review "of certain administrative activities in Bethesda during the past two years." At the time Frederickson sought and was granted a leave of absence.

Robert A. Potter, a Hughes spokesman, said yesterday that the review by inside and outside lawyers has been completed, but he refused to disclose details or answer further questions about Frederickson's departure. Thorn and other members of the board could not be reached for comment.

Fredrickson said in an interview yesterday that the six-month review turned up no evidence of wrongdoing. He said the lawyers performed an "extensive review of how the institute was run." Their inquiry included the costs of locating in new headquarters in Bethesda; expenditures on renovating a building on NIH's Bethesda campus to house Hughes-sponsored researchers, and allegations of conflict of interest involving Fredrickson and his wife.

He said the lawyers examined whether he and his wife had received funds from vendors used by the institute. "There was no such thing," Fredrickson said. "The investigation revealed substantially nothing."

Fredrickson, who was named president of the institute in 1984, did acknowledge an increasingly acrimonious conflict with the board over the administration of the institute and his management style, especially his highly public efforts to promote the institute. The differences widened to the point where he felt he had to leave, he added.

"There were just a lot of differences in how I did things . . . . There wasn't any single special issue, just general matters," Fredrickson said, adding that the disagreements included which staff to hire and what furniture to buy. "My work in large measure being done, I think it better for me to bow out."

Scientific friends and colleagues of Fredrickson said yesterday they were stunned by his resignation, given the major changes he has helped implement at the Hughes Institute.

Some said they had understood that a major source of conflict with the board had been the extensive participation of his wife, Henrietta Fredrickson, in various institute affairs, including the building of a new dormitory for NIH researchers funded by Hughes. An article this week in The Scientist, a newspaper for the science community, said Henrietta Fredrickson attended numerous board meetings and pushed through a lavish plan to decorate Donald Fredrickson's offices.

"I had heard that there was some concern over Mrs. Fredrickson's interest or involvement in the management of the program," said Dr. Theodore Cooper, vice chairman of Upjohn Co. and a long-time friend of Fredrickson's.

"My perception was that {Fredrickson} was getting very high marks for what he was doing at the institute programatically," Cooper added. "His standing is tremendous." Another associate, Dr. Joseph E. Rall, NIH deputy director, added: "I can imagine that he took them farther than they wanted to go. I can imagine he got tired of it."

With the dramatic increase in cash from the 1985 sale of Hughes Aircraft, the institute has started to expand its operations and patch up relations with the Internal Revenue Service, which has for years questioned the institute as a device designed to shield the company from taxes. Last March, the institute reached a settlement with the IRS.