We conducted an arbitrary fragment length polymorphism (AFLP) analysis followed by tests of association to search for potential genetic markers associated with resistance to infection by Vibrio vulnificus and Perkinsus marinus in a sample of North Carolina oysters. We used 48 AFLP markers and found significant associations for two of these markers with the incidence of infection of P. marinus and two separate markers associated with the magnitude of infection of V. vulnificus. Further, there was evidence of epistatic interactions of genes affecting infection levels of both pathogens. This suggests existence of genes or groups of genes that are located on chromosome fragments close to the identified AFLP markers and that act directly or indirectly (through epistasis) to control the levels of infection by these microorganisms in oysters. The impact of the direct and epistatic effects of these unknown genes on infection level variability amounted to about 40% for both P. marinus and V. vulnificus. This study demonstrates the utility of the AFLP approach to identify genetic markers of pathogen/parasite resistance in eastern oysters. However, the identified AFLP markers are considered preliminary and suggestive only because of the limited sample size analyzed in this study. Further studies using this approach on a larger sample size are required to identify a set of robust molecular markers that would serve in a marker-supported breeding program designed to improve the quality of the oyster stock.