In the physiologic modeling of dynamic positron emission tomography (PET) data, one is typically interested in the average reconstructed activity for voxels within the boundaries of some volume of interest (VOI), the uncertainty of this value, and possibly correlations with other VOIs. These calculations have been partially carried out in the past by drawing appropriate 2D regions on a number of reconstructed images in a PET volume, and then summing the voxel values within these regions. Summing voxel values in this fashion provides a value for activity within a volume, but does not allow calculation of the statistical uncertainty. To perform the latter task, calculations must be performed on the raw tomographic data, and thus the 2D regions must be specified on the originally acquired tomographic slices. We have developed software enabling clinicians to specify regions along any preferred viewing axis, and yet perform calculations on these regions to obtain the complete VOI covariance matrix. In this process, 2D regions are first drawn on slices of arbitrary orientation. Stacks of these regions are then tiled together to form a closed 3D surface model for each VOI. Cross sections of these VOIs in the originally acquired orientation are obtained by intersecting the 3D surface models with a series of appropriately transformed slicing planes. The resliced regions are then projected into tomographic sinogram space and the activity and uncertainty is calculated for each region. Knowledge of the complete covariance matrix allows combination of these 2D region activity values into 3D volume activity values and uncertainties.