This study aimed to assess the mechanisms of innate immune function responses to silica-coated iron oxide nanoparticle functionalized with dithiocarbamate groups (IONP) exposure alone and its associated mercury (Hg) in European eel (Anguilla anguilla L.) phagocytes isolated from peritoneum (P-phagocytes), gill (G-phagocytes), head kidney (HK-phagocytes) and spleen (S-phagocytes). The study evaluated viability, phagocytosis, oxidative burst activity (OBA) and lipid peroxidation (LPO). Four groups were made: (1) 2 × 10(6) phagocytes + RPMI-1640 (control), (2) 2 × 10(6) phagocytes + IONP (2.5 mg L(-1)), (3) 2 × 10(6) phagocytes + Hg (50 μg L(-1)) and (4) 2 × 10(6) phagocytes + IONP + Hg. Samplings were performed at 0, 2, 4, 8, 16, 24, 48 and 72 h of exposure. A. anguilla P-, G-, HK- and S-phagocytes in vitro exposure to IONP alone revealed either increased (except HK-phagocytes at 16 h) or no change in viability, suggesting that the cells are metabolically active and resistant to IONP exposure alone. In terms of phagocytes overactivation and reactive oxygen species (ROS) production as an indirect mechanism of immunotoxicity, the phagocytes responded in the following manner: P- > S- > HK- = G-phagocytes for IONP exposure alone, S- > HK- > P- = G-phagocytes for Hg exposure alone and HK- > G- = S- > P-phagocytes for concomitant exposure. Overall, considering Hg as a surrogate for metals and its association with IONP, as well as the likelihood that it could pose a serious threat to aquatic organisms by modulating their immune defense mechanisms if accidentally discharged into the aquatic environment, current results suggest that the step of IONP-metal complex removal must not be underrated and should be processed without any more ado.