X-ray fluorescence analysis (XRF) is a non-invasive method that can be used for in vivo determination of thyroid iodine content. System calibrations with phantoms resembling the neck may give misleading results in the cases when the measurement situation largely differs from the calibration situation. In such cases, Monte Carlo (MC) simulations offer a possibility of improving the calibration by better accounting for individual features of the measured subjects. This study investigates the prospects of implementing MC simulations in a calibration procedure applicable to in vivo XRF measurements. Simulations were performed with Penelope 2005 to examine a procedure where a parameter, independent of the iodine concentration, was used to get an estimate of the expected detector signal if the thyroid had been measured outside the neck. An attempt to increase the simulation speed and reduce the variance by exclusion of electrons and by implementation of interaction forcing was conducted. Special attention was given to the geometry features: analysed volume, source–sample-detector distances, thyroid lobe size and position in the neck. Implementation of interaction forcing and exclusion of electrons had no obvious adverse effect on the quotients while the simulation time involved in an individual calibration was low enough to be clinically feasible.