The fungal cereal pathogen Fusarium graminearum produces deoxynivalenol (DON) during infection. The mycotoxin DON is associated with Fusarium head blight (FHB), a disease that can cause vast grain losses. Whilst investigating the suitability of Brachypodium distachyon as a model for spreading resistance to F.graminearum, we unexpectedly discovered that DON pretreatment of spikelets could reduce susceptibility to FHB in this model grass. We started to analyse the cell wall changes in spikelets after infection with F.graminearum wild-type and defined mutants: the DON-deficient tri5 mutant and the DON-producing lipase disruption mutant fgl1, both infecting only directly inoculated florets, and the mitogen-activated protein (MAP) kinase disruption mutant gpmk1, with strongly decreased virulence but intact DON production. At 14 days post-inoculation, the glucose amounts in the non-cellulosic cell wall fraction were only increased in spikelets infected with the DON-producing strains wild-type, fgl1 and gpmk1. Hence, we tested for DON-induced cell wall changes in B.distachyon, which were most prominent at DON concentrations ranging from 1 to 100ppb. To test the involvement of DON in defence priming, we pretreated spikelets with DON at a concentration of 1ppm prior to F.graminearum wild-type infection, which significantly reduced FHB disease symptoms. The analysis of cell wall composition and plant defence-related gene expression after DON pretreatment and fungal infection suggested that DON-induced priming of the spikelet tissue contributed to the reduced susceptibility to FHB.