Few studies have been done to determine the toxicity of Nanoparticles (NPs) on marine ecosystems and its effect on the biota. NPs interaction with Salinity, a major environmental factor, needs particular attention. Organisms in the Venice lagoon, the sampling site of this study, are subject to a wide range of salinity, yet little is known about the combined effect of an environmental stressor and NPs. Thus, this work aimed to evaluate the toxicological effects of salinity/NPs interaction. The study was conducted in two species: R. decussatus, native clams from the lagoon, and R. philippinarum, a clam deliberately introduced that has supplanted the native species. The two clams were exposed for 7 days to nZnO, nTiO2 and fullerene C60 (1 μg/L), at three salinity levels (18, 28, 38), with tissue collections after 1, 3 and 7 days. Biomarkers were evaluated in hemolymph, gills and digestive gland; RNA/DNA ratio and proteins were measured in foot tissue. R. decussatus had a significant increase in micronuclei, nuclear abnormalities, CAT and SOD at higher salinity, whereas LDH and NRU showed significant increases at low salinity. GST showed PCC showed increases at high salinity. RNA/DNA ratio did not show significant differences and the proteins presented significant decreases in medium and high salinity. R. philippinarum showed significant differences in micronuclei and nuclear abnormalities at high salinity and LDH and NRU with differences at lower salinity. CAT showed different values at low and high; SOD showed differences in the higher salinities. GST, LPO and PCC levels showed differences in the lower salinities. RNA/DNA ratio and proteins presented no differences. The results support the premise that R. decussatus is less resistant than the invasive species. This work is among the first to try to determine if the combination salinity/NPs have a synergistic effect on aquatic organisms.