In many countries there are increasing calls for the benefits of genetically modified organisms (GMOs) to be considered as well as the risks, and for a risk-benefit analysis to form an integral part of GMO regulatory frameworks. This trend represents a shift away from the strict emphasis on risks, which is encapsulated in the Precautionary Principle that forms the basis for the Cartagena Protocol on Biosafety, and which is reflected in the national legislation of many countries. The introduction of risk-benefit analysis of GMOs would be facilitated if clear methodologies were available to support the analysis. Up to now, methodologies for risk-benefit analysis that would be applicable to the introduction of GMOs have not been well defined. This paper describes a relatively simple semi-quantitative methodology that could be easily applied as a decision support tool, giving particular consideration to the needs of regulators in developing countries where there are limited resources and experience. The application of the methodology is demonstrated using the release of an insect resistant maize variety in South Africa as a case study. The applicability of the method in the South African regulatory system is also discussed, as an example of what might be involved in introducing changes into an existing regulatory process.