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The goal of this study was to assess the impact of set-up uncertainty on compliance with the objectives and constraints of an intensity modulated radiation therapy protocol for early stage cancer of the oropharynx. As the convolution approach to the quantitative study of set-up uncertainties cannot accommodate either surface contours or internal inhomogeneities, both of which are highly relevant to sites in the head and neck, we have employed the more resource intensive direct simulation method. The impact of both systematic (variable from 0 to 6 mm) and random (fixed at 2 mm) set-up uncertainties on compliance with the criteria of the RTOG H-0022 protocol has been examined for eight geometrically complex structures: CTV66 (gross tumour volume and palpable lymph nodes suspicious for metastases), CTV54 (lymph node groups or surgical neck levels at risk of subclinical metastases), glottic larynx, spinal cord, brainstem, mandible and left and right parotids. In a probability-based approach, both dose–volume histograms and equivalent uniform doses were used to describe the dose distributions achieved by plans for two patients, in the presence of set-up uncertainty. The equivalent uniform dose is defined to be that dose which, when delivered uniformly to the organ of interest, will lead to the same response as the non-uniform dose under consideration. For systematic set-up uncertainties greater than 2 mm and 5 mm respectively, coverage of the CTV66 and CTV54 could be significantly compromised. Directional sensitivity was observed in both cases. Most organs at risk (except the glottic larynx which did not comply under static conditions) continued to meet the dose constraints up to 4 mm systematic uncertainty for both plans. The exception was the contra lateral parotid gland, which this protocol is specifically designed to protect. Sensitivity to systematic set-up uncertainty of 2 mm was observed for this organ at risk in both clinical plans.