Purpose To investigate the accuracy and robustness of commercial algorithms for Deformable Image Registration (DIR) to propagate regions of interest (ROIs), against image quality typical of Cone Beam CT (CBCT) and Megavoltage Cone-beam CT (MVCT) images, using computational phantoms based on real head and neck (HN) patient images. Methods Eleven institutions joined the study with five commercial DIR solutions. Three real patient data-sets from different on board imaging devices (OBI by Varian, XVI by Elekta, and MVCT by Tomotherapy) were used with different image quality. Two specific Deformation Vector Fields (DVF) with realistic level of deformations, were generated with a dedicated software and then applied to each data-set. The accuracy of the algorithms was assessed by comparing the DIR-mapped ROIs from each center with those of reference, using the Dice Similarity Coefficient (DSC) and Mean Distance to Conformity (MDC) metrics. Prognostic factors of DIR performances were carried out. Results Based on more than 700 DIR-mapped ROIs the 4-way ANOVA analysis states that DIR algorithm, image quality and organ type are significant predictors of DIR performances. A slightly dependence from applied DVF is detected (p = 0.035) with a post hoc test. Putting together all CI data of all institutions for the first DVF, the mean CI was 0.88 ± 0.05 (1 SD), and the mean MDC is 0.38 ± 0.96 (1 SD); for the second DVF, the mean CI was 0.86 ± 0.11 (1 SD), and the mean MDC is 0.43 ± 1.08 (1 SD). The thyroid, located near the FOV border, was the underperformer organ with large errors (unacceptable). All other organs were mapped with an acceptable accuracy (at voxel size level). One imaging system performs statistically better than the others, and one algorithm produced unsatisfactory results respect all the others. Conclusions This work studies the impact of CBCT and MVCT image quality on DIR performance in a ground truth provided scenario. Clinical issues like Adaptive Radiation Therapy (ART) need accurate and robust DIR software. The reported result highlight that in HN district the image quality and the implemented algorithm are strictly related to DIR performances.