[11C](+)McN-5652 is an established positron emission tomography tracer used to assess serotonergic transporter density. Several methods have been used to analyze [11C](+)McN-5652 data; however, no evaluation of candidate methods has been published in detail yet. In this study, compartmental modeling using a one-tissue compartment model (K1, k2"), a two-tissue compartment model (K1 to k4), and a noncompartmental method that relies on a reference region devoid of specific binding sites were assessed. Because of its low density of serotonergic transporters, white matter was chosen as reference. Parameters related to transporter density were the total distribution volume DV" (= K1/k2", one tissue compartment), DVtot, (=K1/k1' (1 + k3/k4), two tissue compartments), and Rv (= k3'/k4, noncompartmental method). The DV", DVtot, and Rv values extended over a similar range and reflected the known pattern of serotonergic transporters. However, all parameters related to transporter density were markedly confounded by nonspecific binding. With regard to K1, the one-tissue compartment model yielded markedly lower values, which were, however, more stable. The minimal study duration needed to determine stable values for the distribution volume was approximately 60 minutes. The choice of the method to analyze [11C](+)McN-5652 data depends on the situation. Parametric maps of Rv are useful if no information on K1 is needed. If compartmental modeling is chosen, both the one- and the two-tissue compartment models have advantages. The one-tissue compartment model underestimates K1 but yields more robust values. The distribution volumes calculated with both models contain a similar amount of information. None of the parameters reflected serotonergic transporter density in a true quantitative manner, as all were confounded by nonspecific binding.