Diverse animals have evolved an ability to collect antimicrobial compounds from the environment as a means of reducing infection risk. Honey bees battle an extensive assemblage of pathogens with both individual and “social” defenses. We determined if the collection of resins, complex plant secretions with diverse antimicrobial properties, acts as a colony-level immune defense by honey bees. Exposure to extracts from two sources of honey bee propolis (a mixture of resins and wax) led to a significantly lowered expression of two honey bee immune-related genes (hymenoptaecin and Am Eater in Brazilian and Minnesota propolis, respectively) and to lowered bacterial loads in the Minnesota (MN) propolis treated colonies. Differences in immune expression were also found across age groups (third-instar larvae, 1-day-old and 7-day-old adults) irrespective of resin treatment. The finding that resins within the nest decrease investment in immune function of 7-day-old bees may have implications for colony health and productivity. This is the first direct evidence that the honey bee nest environment affects immune-gene expression.