The Wits Reproductive Health and HIV Institute (WRHI) was founded in 1994 as a joint initiative between Department of Obstetrics and Gynaecology of the Wits Faculty of Health Sciences and the Greater Johannesburg Metropolitan Council. The concept of the WRHI was developed by Professor Helen Rees who had worked with the African National Congress on the development of its new health policies before the 1994 democratic elections. At its inception in 1994, a major objective of RHRU was to provide the newly elected democratic government with technical support for policy formulation and to develop a relevant research agenda in the field of reproductive health.

In 2000, the WRHI was made an official research unit of the Wits Department of Obstetrics and Gynaecology. In 2002 the WRHI was awarded the status of a WHO Collaborating Centre status by WHO’s Afro region and by WHO’s headquarters in Geneva. In 2007, WRHI was redesignated as a collaborating centre for the Reproductive Health and Research Division of WHO, and has recently become a collaborating centre for the division for the Integrated Management of Adult and Adolescent Illness (IMAI).

Since 1994 the WRHI has significantly expanded its scope of work, number of projects and programmes and staff complement. The expansion of the WRHI's research and technical support activities has resulted in it's growth of the Unit into new research sites and into additional provinces. In 2006, the WRHI moved its National Office to Hillbrow in the Inner City of Johannesburg, where offices, research space for clinical trials, a major training centre and a community care centre have been established. In 2008 an WRHI office was established in Mafikeng, North-West Province, to support the organisation's health systems strengthening activities with the provincial health department.

Having started with a focus on reproductive health, the Institute expanded its portfolio into HIV research and health service interventions and later expanded further into a wider range of sexually transmitted infections and HIV co-infections including TB, and the WRHI is now responsible for infectious diseases in the tertiary hospital facility of the Charlotte Maxeke Johannesburg Academic Hospital. In parallel to its research portfolio, WRHI has developed a major programme of health systems strengthening that targets HIV and TB treatment and prevention.

 After 16 years the WRHI has earned an international reputation in the field of reproductive health, in HIV and in infectious diseases especially as they interface with HIV and reproductive health.

In 2010, in recognition of its work, WRHI was awarded Institute status by Wits University. In October 2010,WRHI was formed as a result of the merger between RHRU and ECHO, another Wits University research unit specialising in HIV in the paediatric population.