Phantom experiments and simulations were performed to evaluate the significance of different error sources in a clinical registration procedure for brain SPET and MRI based on external markers. The results from the phantom experiments were used to adjust the error model for simulations. In the phantom experiments, 13-14 external markers were attached to the surface of a three-dimensional brain phantom for computing registration. Three internal test markers were used to estimate the accuracy of registration. The phantom was imaged with two different SPET and MRI devices. The mean root-mean-squared (RMS) residual of the locations of the test markers after registration using different combinations of four external markers varied from 3.5 +/- 1.0 to 5.2 +/- 1.3 mm depending on the imaging equipment and parameters used. The accuracy improved with an increasing number of external markers, from 3.2 +/- 0.5 to 4.9 +/- 0.5 mm for 6 markers and from 3.1 +/- 0.1 to 4.7 +/- 0.1 mm for 13 markers. In simulations, the external markers had an error comparable to the corresponding error in the phantom experiments. The error in the test markers was varied independently of that of the external markers. When the locating error of the test markers was removed, about 2 mm of the residuals of the test markers were found to come from this source. When an error comparable to the resolution of the original images (7-10 mm for SPET, 2 mm for MRI) was included in the test markers, the largest mean RMS residual after registration was smaller than the resolution error (8.8 +/- 1.1 mm). This was due to the accuracy of localization of the external markers and the fact that the direction of the error was random for each marker. The size of the registration error of an image volume was site-dependent, being minimal near the centre of mass of the external markers. When comparing the error with the spatial resolution of SPET, it was concluded that the accuracy of registration is not the limiting factor in region-of-interest analysis of registered images, provided that the design and attachment of the marker system are appropriate.