The thermal processing of milk is negatively impacted by fouling, which decreases the rate of heat transfer and increases the frequency of cleaning. Small-scale tools that can predict fouling on larger scales are crucial to understanding and mitigating fouling. In this work, milk fouling is compared between the submicron scale, using a high-pressure high-temperature quartz crystal microbalance with dissipation (HPHT QCM-D), and the pilot scale. Fouling rates are monitored in situ and foulants are characterized ex situ using Raman spectroscopy and atomic force microscopy (AFM). The results reveal that a proteinaceous foulant is formed on both scales. Also, a gradient in the magnitude of fouling is observed at both scales as a function of the local residence time and temperature with the greatest amount of fouling observed for the smallest local residence time and at the highest temperature (132 °C). The results suggest a scale-up factor of approximately 70−120 times when converting between QCM-D and pilot-scale fouling thicknesses. Similarities in the foulant properties and fouling rates support QCM-D as a viable technology for scale-up studies of milk fouling.