OBJECTIVE: This [C]flumazenil (FMZ) study evaluates the performance of various parametric analysis methods and their ability to detect statistically significant group differences. METHODS: Dynamic 60-min FMZ scans were performed in eight healthy and nine individuals with major depressive disorder. Parametric volume of distribution (VT) images were generated using a basis function method (BFM) implementation of the single tissue compartment model (1T) and Logan plot analysis, both with a metabolite-corrected arterial plasma input function. Parametric binding potential (BPND) images were generated using multilinear reference tissue methods (MRTM0-4), reference Logan and receptor parametric mapping (RPM1-2), with pons as a reference region. Standardized uptake value (SUV) and SUV ratio-to-pons (SUVr) images were calculated over the time interval 30-40 and 20-60 min postinjection. The resulting VT, BPND, SUV and SUVr values were compared with nonlinear regression values, using both the 1T model and the simplified reference tissue model. Statistical parametric mapping (SPM5) was used to detect group differences, with an emphasis on the bilateral parahippocampal gyri. RESULTS: BFM was more accurate than Logan, but showed more variability. Both RPM methods and MRTM2 showed the best average correlation with the simplified reference tissue model. In using SPM, SUV and SUVr images provided the best contrast between groups in the parahippocampal gyri, but provided large underestimation and overestimation in quantitative comparisons. BFM and RPM methods allowed for the determination of perfusion effects. CONCLUSION: Parametric Logan VT, MRTM2 and RPM1-2 BPND methods allow the best quantitative comparison of FMZ binding between groups and show good discriminating performance in SPM analysis.