Preferential pathways can be significant vapor intrusion (VI) contributors, causing potentially higher inhalation risk to residents of affected buildings than that arising through traditional intrusion pathways. To assess land drains as a preferential pathway, a three-dimensional model, validated using data from a 4-yr field study, was used to study the roles of subfoundation soil permeability on soil gas flow and indoor depressurization. Results indicated that it is almost impossible for an indirect preferential pathway like a land drain ending in subfoundation soils with a permeability <10−11 m2 to affect indoor air quality if the land drain connects to a source with the same vapor concentration as that of the groundwater source beneath the building. An equation was developed to estimate the threshold permeability. We also found that even after the preferential pathway was identified using indoor depressurization (also known as controlled pressure method [CPM]) and then turned off, the influence of the preferential pathway and indoor depressurization on indoor concentration might last for months, although it may not be significant (i.e., may not exceed one order of magnitude, in this study). In the absence of such a preferential VI pathway, CPM may actually reduce indoor air concentrations of contaminants below those present under natural indoor pressure conditions, due to the emission rate limit determined by the upward diffusion rate from the vapor source. Our study highlights the role of measuring subfoundation soil permeability to soil gas flow in site investigations and warns practitioners about the possible mischaracterization of indoor air concentration after applying CPM in the absence of a preferential pathway.