The aim of this work was to evaluate the microbiological quality of striped venus clams (Chamelea gallina L.) harvested in the north Adriatic Sea during an 8-year monitoring period. A total of 387 samples were analyzed to assess the presence of Escherichia coli. Environmental parameters (salinity, pH, dissolved oxygen, seawater temperature, and freshwater outflow) were collected to find out a possible relationship between the E. coli counts and environmental factors. The results evidenced that the microbiological quality of the clams was good, with only about 5% of the samples not complying with European and Italian regulations for this product, that is, with E. coli counts higher than 230 most probable number (MPN) per 100 g of flesh and intravalvar liquid. Statistical analyses revealed a relationship between microbial contamination and the season and water temperature, probably due to the difference in the filtering activity of the mollusks. However, the main factor affecting the E. coli concentration in the clams turned out to be the flow rate of Marecchia, the major river that reaches the sea in the area of harvesting. In fact, a model fitted to evaluate the probability of finding a higher E. coli count in relation to the environmental parameters evidenced that it was an increase of the level of the Marecchia led to a higher probability of elevated E. coli contamination. This result could be explained by the higher supply of both nutrients and coliforms (including E. coli) when the river is higher and by the anthropogenic characteristics of the lands crossed by the river.