Simple SummarySea turtles are susceptible to several herpesviruses that are linked to dermatologic diseases, including fibropapillomatosis (FP) and lung-eye-trachea disease. Aside from obvious skin lesions, a number of other sublethal impacts occur in response to these diseases, such as reduced immune function. In this study, we found no relationship between disease presence or severity and T-cell proliferation in green turtles from Florida, USA, at least until the moderate stages of FP; however, natural killer cell activity, a measure of innate immune function, was significantly reduced in turtles with FP compared to tumor-free individuals. This is the first study to examine natural killer cell activity in relation to FP, improving upon our understanding of altered immune system function associated with this disease.Chelonid alphaherpesviruses 5 and 6 (ChHV5 and ChHV6) are viruses that affect wild sea turtle populations. ChHV5 is associated with the neoplastic disease fibropapillomatosis (FP), which affects green turtles (Chelonia mydas) in panzootic proportions. ChHV6 infection is associated with lung-eye-trachea disease (LETD), which has only been observed in maricultured sea turtles, although antibodies to ChHV6 have been detected in free-ranging turtles. To better understand herpesvirus prevalence and host immunity in various green turtle foraging aggregations in Florida, USA, our objectives were to compare measures of innate and adaptive immune function in relation to (1) FP tumor presence and severity, and (2) ChHV5 and ChHV6 infection status. Free-ranging, juvenile green turtles (N = 45) were captured and examined for external FP tumors in Florida’s Big Bend, Indian River Lagoon, and Lake Worth Lagoon. Blood samples were collected upon capture and analyzed for ChHV5 and ChHV6 DNA, antibodies to ChHV5 and ChHV6, in vitro lymphocyte proliferation using a T-cell mitogen (concanavalin A), and natural killer cell activity. Despite an overall high FP prevalence (56%), ChHV5 DNA was only observed in one individual, whereas 20% of turtles tested positive for antibodies to ChHV5. ChHV6 DNA was not observed in any animals and only one turtle tested positive for ChHV6 antibodies. T-cell proliferation was not significantly related to FP presence, tumor burden, or ChHV5 seroprevalence; however, lymphocyte proliferation in response to concanavalin A was decreased in turtles with severe FP (N = 3). Lastly, green turtles with FP (N = 9) had significantly lower natural killer cell activity compared to FP-free turtles (N = 5). These results increase our understanding of immune system effects related to FP and provide evidence that immunosuppression occurs after the onset of FP disease.