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Among accumulating knowledge of invertebrate immune-like responses, antiviral mechanisms in mollusks remain poorly understood. Pinctada birnavirus (PiBV) infects the mantle epithelial cells of the pearl oyster (Pinctada fucata), causing mass mortality of juveniles during high-temperature periods. Here, we examined immune memory-like responses of pearl oysters to PiBV reinfection. At a high temperature (24–25 °C), experimental infection caused ~80% mortality, whereas mortality remained <30% and did not differ significantly from uninfected controls at a lower temperature (18–20 °C). Juveniles that survived infection at the low temperature and were subsequently reinfected at the higher temperature showed 10% mortality, which was significantly lower than the ~50% observed in naïve oysters infected under the same conditions. At 28 days post-infection at the lower temperature, oysters exhibited gene expression profiles distinct from those of naïve oysters. Ex vivo infection demonstrated significantly reduced PiBV replication in mantle explants from previously infected oysters compared with those from naïve individuals. These findings indicate that P. fucata acquires resistance to PiBV reinfection, and at least part of this resistance is mediated within the mantle, independently of other tissues. Culture supernatants of mantle explants from previously infected oysters were positive for viral genomic RNA even without viral inoculation, suggesting that persistent infection may contribute to the maintenance of immune-like responses.