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A novel application of a knowledge-based fuzzy logic technique was used in this study to derive margins for use in external beam radiotherapy. Radiotherapy uncertainties including set-up, delineation and organ motion-induced errors were used to calculate the changes in prostate radiobiological indices for treatment plans using stepped increments of margin sizes. The results were used to formulate the rule base and membership functions for the Sugeno type fuzzy inference system. The application of a convolution technique was found to improve the imprecision and smoothness of the original fuzzy output. Good agreement was obtained between the proposed fuzzy model margin and currently used radiotherapy margins. The new margin was applied in a prostate cancer treatment planning example and the results compared very well to current techniques.