The purpose of the present study was to evaluate the performance of various parametric methods for quantification of [(18)F]FDDNP studies. All parametric methods tested were based on the use of a reference tissue and they were compared with the simplified reference tissue model (SRTM), as previously it has been shown that SRTM is the method of choice for analysing [(18)F]FDDNP studies, even when an arterial plasma input function is available. The following parametric methods were evaluated: receptor parametric mapping (basis function implementation of SRTM; with and without fixing the reference tissue efflux rate constant k'(2)), reference Logan and several multi-linear reference tissue methods (again with and without fixing k'(2)). Simulations were used to assess the effects of variation in relative flow (R(1)), fractional blood volume (V(b)) and binding potential (BP(ND)) on precision and accuracy of estimated BP(ND). For clinical data, best performance was obtained using receptor parametric mapping (RPM2) and one of the multi-linear reference tissue models (MRTM2), with k'(2) being fixed in both methods. These models showed good correlation with SRTM, their BP(ND) results were less affected by noise and images showed good contrast. Furthermore, in simulations, RPM2 and MRTM2 provided the most accurate and precise BP(ND) estimates. RPM2 and MRTM2 are the methods of choice for parametric analysis of [(18)F]FDDNP studies.