ZnO nanoparticles (nZnO) are released into the coastal environment from multiple sources, yet their toxicity to marine organisms is not well understood. We investigated the interactive effects of salinity (normal 15, low 5, and fluctuating 5-15) and nZnO (100μgl^-1) on innate immunity of the blue mussels Mytilus edulis from a brackish area of the Baltic Sea. Exposure to ionic Zn (100μgl^-1) was used to test whether the toxic effects of nZnO can be attributed to the potential release of Zn²⁺. Functional parameters and the expression of key immune-related genes were investigated in the mussels exposed to nZnO or ionic Zn under different salinity regimes for 21 days. nZnO exposures elevated hemocyte mortality, suppressed adhesion, stimulated phagocytosis, and led to an apparent increase in lysosomal volume. At salinity 15, nZnO suppressed the mRNA expression of the Toll-like receptors TLRb and c, C-lectin, and the complement system component C3q indicating impaired ability for pathogen recognition. In contrast, the mRNA levels of an antimicrobial peptide defensin increased during nZnO exposure at salinity 15. At fluctuating salinity (5-15), nZnO exposure increased expression of multiple immune-related genes in hemocytes including the complement system components C1 and C3q, and the Toll-like receptors TLRa, b and c. Low salinity (5) had strong immunosuppressive effects on the functional and molecular immune traits of M. edulis that overshadowed the effects of nZnO. The salinity-dependent modulation of immune response to nZnO cannot be attributed to the differences in the aggregation or solubility of nZnO, and likely reflects the interaction of the toxic effects of nanoparticles and physiological effects of the osmotic stress. These findings have implications for the environmental risk assessment of nanomaterials and the development of the context-specific biomarker baselines for coastal pollution monitoring. (C) 2020 Elsevier B.V. All rights reserved.