© 2020 The Authors. Medical Physics published by Wiley Periodicals LLC on behalf of American Association of Physicists in Medicine. Purpose: Geant4 is a multi-purpose Monte Carlo simulation tool for modeling particle transport in matter. It provides a wide range of settings, which the user may optimize for their specific application. This study investigates GATE/Geant4 parameter settings for proton pencil beam scanning therapy. Methods: GATE8.1/Geant4.10.3.p03 (matching the versions used in GATE-RTion1.0) simulations were performed with a set of prebuilt Geant4 physics lists (QGSP_BIC, QGSP_BIC_EMY, QGSP_BIC_EMZ, QGSP_BIC_HP_EMZ), using 0.1mm-10mm as production cuts on secondary particles (electrons, photons, positrons) and varying the maximum step size of protons (0.1mm, 1mm, none). The results of the simulations were compared to measurement data taken during clinical patient specific quality assurance at The Christie NHS Foundation Trust pencil beam scanning proton therapy facility. Additionally, the influence of simulation settings was quantified in a realistic patient anatomy based on computer tomography (CT) scans. Results: When comparing the different physics lists, only the results (ranges in water) obtained with QGSP_BIC (G4EMStandardPhysics_Option0) depend on the maximum step size. There is clinically negligible difference in the target region when using High Precision neutron models (HP) for dose calculations. The EMZ electromagnetic constructor provides a closer agreement (within 0.35 mm) to measured beam sizes in air, but yields up to 20% longer execution times compared to the EMY electromagnetic constructor (maximum beam size difference 0.79 mm). The impact of this on patient-specific quality assurance simulations is clinically negligible, with a 97% average 2%/2 mm gamma pass rate for both physics lists. However, when considering the CT-based patient model, dose deviations up to 2.4% are observed. Production cuts do not substantially influence dosimetric results in solid water, but lead to dose differences of up to 4.1% in the patient CT. Small (compared to voxel size) production cuts increase execution times by factors of 5 (solid water) and 2 (patient CT). Conclusions: Taking both efficiency and dose accuracy into account and considering voxel sizes with 2 mm linear size, the authors recommend the following Geant4 settings to simulate patient specific quality assurance measurements: No step limiter on proton tracks; production cuts of 1 mm for electrons, photons and positrons (in the phantom and range-shifter) and 10 mm (world); best agreement to measurement data was found for QGSP_BIC_EMZ reference physics list at the cost of 20% increased execution times compared to QGSP_BIC_EMY. For simulations considering the patient CT model, the following settings are recommended: No step limiter on proton tracks; production cuts of 1 mm for electrons, photons and positrons (phantom/range-shifter) and 10 mm (world) if the goal is to achieve sufficient dosimetric accuracy to ensure that a plan is clinically safe; or 0.1 mm (phantom/range-shifter) and 1 mm (world) if higher dosimetric accuracy is needed (increasing execution times by a factor of 2); most accurate results expected for QGSP_BIC_EMZ reference physics list, at the cost of 10–20% increased execution times compared to QGSP_BIC_EMY.