(R)-[(11)C]PK11195 ([1-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl]-3-isoquinoline carboxamide) is a ligand for the peripheral benzodiazepine receptor, which, in the brain, is mainly expressed on activated microglia. Using both clinical studies and Monte Carlo simulations, the aim of this study was to determine which tracer kinetic plasma input model best describes (R)-[(11)C]PK11195 kinetics. Dynamic positron emission tomography (PET) scans were performed on 13 subjects while radioactivity in arterial blood was monitored online. Discrete blood samples were taken to generate a metabolite corrected plasma input function. One-tissue, two-tissue irreversible, and two-tissue reversible compartment models, with and without fixing K(1)/k(2) ratio, k(4) or blood volume to whole cortex values, were fitted to the data. The effects of fixing parameters to incorrect values were investigated by varying them over a physiologic range and determining accuracy and reproducibility of binding potential and volume of distribution using Monte Carlo simulations. Clinical data showed that a two-tissue reversible compartment model was optimal for analyzing (R)-[(11)C]PK11195 PET brain studies. Simulations showed that fixing the K(1)/k(2) ratio of this model provided the optimal trade-off between accuracy and reproducibility. It was concluded that a two-tissue reversible compartment model with K(1)/k(2) fixed to whole cortex value is optimal for analyzing (R)-[(11)C]PK11195 PET brain studies.