Dynamic contrast enhanced (DCE) MRI has emerged as a reliable and diagnostically useful functional imaging technique. DCE protocol typically lasts 3-15 minutes and results in a time series of N volumes. For automated analysis, it is important that volumes acquired at different times be spatially coregistered. We have recently introduced a novel 4D, or volume time series, coregistration tool based on a user-specified target volume of interest (VOI). However, the relationship between coregistration accuracy and target VOI size has not been investigated. In this study, coregistration accuracy was quantitatively measured using various sized target VOIs. Coregistration of 10 DCE-MRI mouse head image sets were performed with various sized VOIs targeting the mouse brain. Accuracy was quantified by measures based on the union and standard deviation of the coregistered volume time series. Coregistration accuracy was determined to improve rapidly as the size of the VOI increased and approached the approximate volume of the target (mouse brain). Further inflation of the VOI beyond the volume of the target (mouse brain) only marginally improved coregistration accuracy. The CPU time needed to accomplish coregistration is a linear function of N that varied gradually with VOI size. From the results of this study, we recommend the optimal size of the VOI to be slightly overinclusive, approximately by 5 voxels, of the target for computationally efficient and accurate coregistration.