PURPOSE: To discuss the first clinical experience with a multiple region of interest (mROI) registration and correction method for high-precision radiotherapy of head-and-neck cancer patients. MATERIALS AND METHODS: 12-13 3D rectangular-shaped ROIs were automatically placed around bony structures on the planning CT scans (n=50 patients) which were individually registered to subsequent CBCT scans. mROI registration was used to quantify global and local setup errors. The time required to perform the mROI registration was compared with that of a previously used single-ROI method. The number of scans with residual local setup error exceeding 5mm/5 degrees (warnings) was scored together with the frequency ROIs exceeding these limits for three or more consecutive imaging fractions (systematic errors). RESULTS: In 40% of the CBCT scans, one or more ROI-registrations exceeded the 5mm/5 degrees . Most warnings were seen in ROI "hyoid", 31% of the rotation warnings and 14% of the translation warnings. Systematic errors lead to 52 consults of the treating physician. The preparation and registration time was similar for both registration methods. CONCLUSIONS: The mROI registration method is easy to use with little extra workload, provides additional information on local setup errors, and helps to select patients for re-planning.