Chamelea gallina is a valuable commercial species in the Mediterranean Sea. The strong fishing pressure on C. gallina in the northern and central Adriatic Sea has paralleled a clear-cut decrease in clam population density and the occurrence of several irregular mortality events. Despite the commercial interest in this species, nothing is known about its genetic sub-structuring at the geographic and/or temporal scale, nor its levels of genetic variability. Analyzing microsatellite genotypes for samples collected in the Adriatic Sea, we detected large geographic genetic homogeneity with gene flow guided by broad scale circulation in the north-south direction. Our results also indicate weak genetic differentiation among size classes at the local and temporal scale. These small genetic differences might be determined by variability of local circulation and reproductive success, partial overlapping generations and high larval mortality rates as suggested by our estimates of the effective number of breeders. In fact, global effective population size estimates over multiple generations are medium-high, but a low number of breeders are responsible for the small clams size class recruitment. Notwithstanding, it was not possible to detect signatures of bottleneck. Future efforts in fishery management should aim to maintain genetic diversity – essential to the long-term sustainability of the resource – and limit effective population size fluctuations while considering the need to improve water quality to avoid mass mortality events.