The Ontario Cancer Institute was established in 1952 by an Act of the Ontario Legislature.

Bill 172, an Act to amalgamate The Toronto Hospital and the Ontario Cancer Institute / Princess Margaret Hospital came into effect on January 1, 1998. The departments consolidated but OCI/PMH was to retain its own identity. The combined oncology program became Ontario Cancer Institute / Princess Margaret Hospital a division of The Toronto Hospital.

The original mandate for the Institute was to plan, construct, and establish buildings to accommodate cancer research, diagnosis and treatment, and the observation of and consultation with cancer sufferers. This mandate was broadened when the Institute was reconstituted by the Cancer Act, 1957, "to maintain, manage and operate a provincial hospital with facilities for cancer research, diagnosis and treatment". Construction at the 500 Sherbourne Street location began in 1954 and the Hospital opened on May 1, 1958 with 87 beds.

<blockquote>"The ... Hospital, as well as being an active treatment hospital, is one of the teaching hospitals affiliated with the University of Toronto. The scientists in the Research Division form the basis of the University's Medical Biophysics Division. Staff physicians also provide consultative and treatment services at the Hospital for Sick Children, St. Michael's Hospital, Sunnybrook Medical Centre and Toronto General Hospital, and attend six consultative and follow-up clinics located at North Bay, Owen Sound, Peterborough, Sault Ste. Marie, Sudbury and Timmins". [The Ontario Cancer Institute incorporating The Princess Margaret Hospital: An Introduction / The Ontario Cancer Institute. - Toronto : Undated, p.1] </blockquote>

The hospital was responsible to the Institute's Board which was made up of representatives from The Ontario Cancer Treatment and Research Foundation, the University of Toronto and its teaching hospitals.

The Ontario Cancer Institute was originally organized into four divisions under the authority of the Institute's Director. These divisions were: clinical services, hospital services, physics, and biological research. The hospital's active and consulting medical staff were grouped under the umbrella of clinical services, while both patient services and administration were grouped under hospital services. The administrative structure of the hospital has undergone various changes over the years. Notably, by 1969, the Division of Hospital Services had been dismantled , and its various departments had been placed under the heading of Administrative Staff.

To mark the visit in 1958 of Her Royal Highness, Princess Margaret, the Government of Ontario named the new hospital "The Princess Margaret Hospital". The hospital is commonly known as the Ontario Cancer Institute/Princess Margaret Hospital (OCI/PMH).

As of November 13, 1995, the Hospital officially moved to 610 University Avenue, and the new hospital facility was recognized by a visit from Her Royal Highness, Princess Margaret, on July 12, 1996. OCI/PMH amalgamated with The Toronto Hospital on January 1, 1998.