Mya arenaria (Softshell Clam) is an important recreational and commercial bivalve in coastal New England, the mid-Atlantic, and elsewhere. The Softshell Clam is a filter feeder that provides a trophic link between planktonic food items and benthic predators. We quantified annual trends of disseminated neoplasia in Softshell Clams in the Hampton–Seabrook estuary in New Hampshire using logistic regression from 3975 individuals collected from 2002 to 2018. There was a negative trend in the incidence of Softshell Clams with non-detectable amounts of neoplastic cells, there was no significant trend in the incidence of stage 1 neoplasia (1–25% neoplastic cells), positive trends in the incidences of stages 2 and 3 (26–50% and 51–75% neoplastic cells), and no significant trends in incidence of stage 4 (76–100% neoplastic cells). The significant changes in neoplasia development suggest that the incidence of the disease is increasing. The lack of a significant trend in the terminal stage 4 neoplasia may be due to the short duration of this stage prior to death. Probabilities of acquiring stages 2 and 3 neoplasia in 2018 were 0.19 and 0.12, respectively. The mean length of Softshell Clams with stage 4 neoplasia was 66.7 mm (min–max = 53.2–78.1 mm), which indicates that terminal neoplasia occurs primarily in reproductive adults. The presence of advanced stages of the disease in sexually mature individuals can reduce the reproductive potential of that population.