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PICALM rs3851179 and CLU rs11136000 have been recently associated with Alzheimer's disease (AD). Investigating the effects of these genetic variants on the resting-state functional connectivity (rsFC) of the hippocampus may provide new insight into AD pathogenesis. We investigated the main effects and interactions of these two genetic variants on hippocampal rsFC in 283 healthy young adults. The hippocampus showed positive rsFC with the default mode network and negative rsFC with the fronto-parietal network. Risk PICALM G-allele carriers showed weaker negative rsFC compared with AA carriers, whereas risk CLU-CC carriers exhibited stronger positive and negative rsFC than T-allele carriers. There existed complex interactions between PICALM and CLU on the negative rsFC of the hippocampus. Moreover, we found an allele-dependent effect of CLU on hippocampal connectivity when an additive genetic model was applied to CLU. Most of these effects remained significant even after controlling for individual ApoE status. Our results suggest that PICALM and CLU risk genotypes exert differential impacts on the hippocampal rsFC in healthy young subjects. The complex interactions between PICALM and CLU should be considered when investigating the impact of these two genetic variants on the brain. [ABSTRACT FROM AUTHOR]