Contaminant exposures in natural systems can be highly variable. This variability is superimposed upon cyclic variability in biological processes. Together, these factors can confound determination of contaminant effects. Long term, multidisciplined studies with high frequency sampling can be effective in overcoming such obstacles. While studying trace metal contamination in the tissues of the clam, Potamocorbula amurensis, in the northern reach of San Francisco Bay, an episode of high Ag concentrations was identified (maximum of 5.5 µg g⁻¹) at two mid-estuary sites. High concentrations were not seen in clams up-estuary (maximum of 1.92 µg g⁻¹) from these sites and were reduced down-estuary (maximum of 2.67 µg g⁻¹). Silver is not common naturally in the environment, so its elevated presence is usually indicative of anthropogenic influences such as municipal and industrial discharge. Monthly sampling of reproductive status of clams characterized the reproductive cycle and differences in the patterns of reproductive activity that corresponded to changes in Ag tissue concentrations. The proportion of reproductive clams was less than 60% during periods when tissue concentrations were high (generally >2 µg g⁻¹). When tissue concentrations of Ag decreased (≤1 µg g⁻¹), the proportion of reproductive clams was 80 to 100%. A comparison between the annual proportion of reproductive clams and annual Ag tissue concentrations showed a significant negative correlation. No other measured environmental variables were correlated with reproductive impairment. The weight-of-evidence approach strongly supports a cause and effect relationship between Ag contamination and reduced reproductive activity in P. amurensis.