Disseminated neoplasia, a diffuse tumor of the hemic system, is characterized in many bivalve mollusks by hemolymph containing 1–100% mitotic hemocytes. Little is known about the onset and chronic distribution of neoplasia in populations of Mya arenaria (Soft-shell Clam), though studies have reported episodic exposure to environmental contaminants or an infectious agent as a potential cause of this disease. Here we provide the first set of continuous data on neoplasia in Soft-shell Clams, from three sites in New England where sediments have been characterized regarding their granulometry, composition, contaminants, and clam densities. When correlating sediment characteristics to terminal neoplasia (76–100% neoplastic or rounded, unattached hemocytes), New Bedford Harbor, MA, which is the most contaminated site, had the highest frequency of treminal neoplasia (maximum of 9.49% ± 0.78 SE), and the most pristine site, Ogunquit, ME, displayed the lowest frequencies (maximum of 0.47% ± 0.05 SE). Correlations of frequency of neoplasia to known environmental contaminants also suggests that fully neoplastic individuals were found only at sites of increased levels of heavy metals, PCBs, and PAHs. In addition, we documented the highest frequency of clams with terminal neoplasia from New Bedford Harbor in December (9.49% ± 0.78 SE) when seawater temperatures were low, and the lowest frequency in July (1.08 ± 0.4 SE) when seawater temperatures were highest. These results may indicate vulnerability of neoplastic clams to seasonal increases in environmental temperature and resulting oxidative stress. Based on shell measurements and a theoretical mathematical age model (which correlates susceptibility to neoplasia with age and sexual maturity), we suggest that the Soft-shell Clam is most susceptible to this disease between one and two years of age (9.5% frequency at 1 year, 22.25% incidence at 1.5 years, and 57.14% incidence at 2 years).