Particle size distribution (PSD) is known to influence product properties such as flowability and compressibility. When producing crystalline lactose, different steps can affect the PSD of the final powder. The aim of this study was to investigate the influence of PSD on caking and the mechanisms involved. Smaller particles showed higher moisture sorption and a greater caking tendency, measured by dynamic vapor sorption and ring shear testing, respectively. Therefore, moisture sorption isotherms appeared as a valuable tool to predict the effect of PSD on humidity caking, as confirmed by the results of ring shear testing. Controlling the amount of fines, characterized by a higher content of impurities, a larger specific surface area and a broader span of the PSD, was found critical to limit caking. More precisely, both the total surface area and the span of the PSD require close attention as they can significantly influence humidity and mechanical caking.