Synergistic/antagonistic effects of multiple contaminants in marine environments are almost completely unexplored. In the present study, we investigated the effects of heavy metals (Zn and Pb) and PCBs on picoplankton abundance, biomass, cell size distribution, and bacterial C production. Natural picoplankton assemblages were exposed to heavy metals (Zn or Pb), organic contaminants (PCBs, Aroclor 1260), and to a mixture of different contaminants. The results of the present study indicate that Zn addition stimulated heterotrophic growth, whereas Pb has a negative impact on heterotrophic picoplankton, particularly significant in the first 24 h. Heavy metals had no effects on the autotrophic component. The addition of Aroclor 1260 had a significant impact on abundance, biomass, and cell size of autotrophic and heterotrophic picoplankton, and reduced significantly bacterial secondary production. Three weeks after PCB treatment, heterotrophic bacteria displayed a clear resilience, both in terms of abundance and biomass, reaching values comparable to those of the controls, but not in terms of bacterial C production. Our results indicate that picoplankton can be sensitive indicators of impact determined by heavy metals and PCBs in coastal marine systems.