Epizootic shell disease (ESD) affects lobsters (Homarus americanus) in eastern Long Island Sound (ELIS) and the near-shore waters of southern New England. Marring the shell of individuals, ESD decreases the economic value of infected lobsters and can lead to mortality in severely affected individuals. ESD tends to be most common in areas around Buzzards Bay, RI, and ELIS, and least prevalent in offshore canyons, off Maine's coast, and in western Long Island Sound (WLIS). To investigate the potential role of the immune system in determining an individual's or population's susceptibility to ESD, the immunocompetence and disease status of lobsters with and without signs of ESD from ELIS, WLIS, and Boothbay Harbor, ME, were assessed during late spring (June) 2007. We also measured internal defense parameters of ELIS lobsters during midsummer (August 2007), early fall (October 2007), and the following spring (June 2008) to assess how lobster immune systems respond temporarily. Despite high interindividual variability in defense-related factors, multivariate analyses showed that lobsters from ELIS presented significantly reduced immune responses relative to lobsters from either WLIS or Maine. Disease severity correlated negatively with several immune parameters, suggesting that the higher prevalence of ESD in ELIS may be related, at least in part, to reduced immunocompetency of ELIS lobsters.