With the aim of reducing carbon emissions and increasing hygrothermal comfort, buildings across the UK are undergoing energy retrofits. With historic buildings, it is important that retrofit actions have a limited negative impact on the building’s fabric and cultural significance. Work to date in the UK has focused on the retrofit of historic solid masonry construction, with little research into the retrofit of historic timber-framed buildings. Changes to these buildings must be managed through the use of established conservation principles. However, where infill panels are beyond repair or have previously been substituted with inappropriate materials, there exists the potential to retrofit a material with a higher thermal performance. Nonetheless, it must be ensured that this retrofit does not create interstitial hygrothermal conditions that could threaten the survival of surrounding historic fabric. In this paper the authors present the hygrothermal simulation and physical monitoring of three different potential replacement infill panels. Results from Glaser calculations, WUFI® Pro and WUFI® 2D are compared to measured results of physical test panels mounted between two climate-controlled chambers. Whilst all three prediction methods successfully identified interstitial condensation where it was measured to occur, major discrepancies existed both between simulated and measured results, and between different simulation methods.