OBJECTIVES: Generic medicines are generally considerably less expensive than branded products and their endorsement can lead to substantial savings in costs. The main objective of the study was to calculate potential cost savings that can be generated by generic substitution of antidepressants within the private health care sector of South Africa. METHODS: Data on computerised medicine claims of patients receiving one or more antidepressants during three consecutive years (i.e. 2004, 2005 and 2006) were elicited from a South African pharmaceutical benefit management company. A non-experimental, quantitative, retrospective drug utilisation review was conducted and data were analysed using the Statistical Analysis System® programme. Potential cost savings defined as the collective amount that could be saved annually by substituting the average price of innovator active substances for that of generic equivalent(s) were computed for criteria-eligible substances in the study population. All costs are expressed in $U.S. RESULTS: A total of 292,071 items (N = 5,982,869) on 273,673 prescriptions (N = 5,213,765) at a total cost of $8,652,289.48 (N=$207,316,483.10) were included in the study. Generic products constituted 58.7% (n = 292,071) of all antidepressants claimed, at a total cost of 28.2% (N = $207,316,483.10) of all incurred costs. With total substitution of the average price of all criteria-eligible innovators, a potential saving of 9.3% (N = $8,652,289.48) of the actual antidepressant cost over the study period, was calculated. CONCLUSIONS: In developing countries with limited health care budgets, such as South Africa, generic substances can be cost-saving treatment alternatives. Health care professionals, third party payers, and patients all have fundamental roles to play in order to encourage greater use of generics. Medicine expenditure can thereby be reduced and access to scarce resources increased, in order to meet the pressing health care needs within South Africa.