The prion protein Met129Val polymorphism has recently been related to human long-term memory with carriers of either the 129MM or the 129MV genotype recalling 17% more words than 129(VV) carriers at 24h following learning. Here, we sampled genotype differences in retrieval-related brain activity at 30min and 24h following learning. Furthermore, genotype groups were compared regarding grey matter concentrations and cognitive profiles. We used event-related functional magnetic resonance imaging (fMRI) during a word recognition task on 12 Met/Met carriers, 12 Val/Met carriers, and 12 Val/Val carriers. These groups were matched for retrieval performance, gender, age, education, and other memory-related genetic polymorphisms. Although retrieval performance was matched, Val carriers exhibited enhanced retrieval-related brain activity at 30min and 24h following learning. At both time lags, correlations between retrieval-related brain activity and retrieval success were negative for Val homozygotes (the more activity, the worse retrieval success), while correlations showed no significance or were positive for Met homozygotes and heterozygotes. These results suggest a less economic use of retrieval-related neural resources in Val relative to Met carriers. Furthermore, Val carriers exhibited higher neocortical grey matter concentrations compared to Met carriers. When controlling for grey matter concentration, genotype effects in retrieval-related brain activity remained significant. Val and Met carriers yielded comparable brain activations for correct rejections of non-studied words and for working memory, which speaks to the specificity of the genotype effect. Findings suggest that the prion protein Met129Val polymorphism affects neural plasticity following learning at a time-scale of minutes to hours.